@article {pmid41478829,
year = {2026},
author = {Meade, J and Mesa, H and Alamgir, S and Bieniecka, I and Liu, L and Zhang, Q},
title = {Synaptic toxicity of OGA inhibitors and the failure of ceperognastat.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100456},
doi = {10.1016/j.tjpad.2025.100456},
pmid = {41478829},
issn = {2426-0266},
abstract = {O-GlcNAcase inhibitors (OGAi) have emerged as a promising therapeutic strategy in Alzheimer's disease (AD) by enhancing O-GlcNAcylation, which competes with tau phosphorylation and reduces tau aggregation. However, the Phase II clinical trial failure of ceperognastat, marked by accelerated cognitive decline in the treatment group, has raised significant safety concerns. Here, we examined the acute synaptic effects of three structurally distinct OGAi compounds-ceperognastat, ASN90, and MK8719-in mouse hippocampal slices. Electrophysiological recordings revealed suppression of both short- and long-term synaptic plasticity, including paired-pulse facilitation/depression and long-term potentiation. Immunohistochemical analysis confirmed disrupted synaptic protein levels (increased PSD-95, reduced Synaptophysin 1) and a biphasic shift in tau phosphorylation. These convergent findings suggest a class-wide synaptotoxic mechanism and call for a great caution in the development of disease-modifying therapies in AD. We argue that preclinical drug screening for synaptic functionality is essential in CNS-targeted therapeutic pipelines.},
}

@article {pmid41478820,
year = {2026},
author = {Wang, P and Wu, X and Sun, F and Zhang, H and Jiang, Y and Wang, Q and Ding, H and Zhou, Y and Liu, F and Liu, H},
title = {Multi-omics integration reveals shared genetic architecture between metabolic markers and gray matter atrophy in Alzheimer's Disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100452},
doi = {10.1016/j.tjpad.2025.100452},
pmid = {41478820},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by widespread gray matter volume (GMV) reductions. Emerging evidence links glucose and lipid metabolic dysregulation to AD pathophysiology. However, the extent to which AD-related GMV alterations and metabolic traits share a common genetic basis remains poorly understood.

OBJECTIVES: To explore the shared genetic architecture between GMV alterations in AD and metabolites related to glucose and lipid metabolism, aiming to provide biological insights into the prevention and treatment of AD.

DESIGN: This is a multimodal, cross-disciplinary study combining neuroimaging meta-analysis, transcriptome-neuroimaging association analysis, conjunctional false discovery rate (conjFDR) analysis, and functional enrichment analysis to identify the shared genetic architecture between AD-related brain structural alterations and metabolic traits.

SETTING: Public databases and European populations.

PARTICIPANTS: The meta-analysis included 49 studies (1945 CE patients and 2598 controls). The largest genome-wide association study (GWAS) summary statistics were used for AD (Ncase = 39,918; Ncontrol =358,140), two glycemic traits-glucose (GLU, N = 459,772) and glycated hemoglobin (HbA1c, N = 146,864), and three lipid traits (N = 1320,016)-high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG).

MEASUREMENTS: We conducted a voxel-based morphometric meta-analysis of GMV in AD by systematically reviewing 49 neuroimaging studies, identified through a literature search in PubMed and Web of Science using a predefined search strategy. Building upon these neuroanatomical findings, we performed a transcriptome-neuroimaging association analysis using data from the Allen Human Brain Atlas to identify genes spatially correlated with GMV alterations. To further explore the shared genetic architecture, we integrated GWAS summary statistics for AD and five metabolic markers using conjFDR analysis. Finally, functional enrichment analyses were performed to elucidate the biological relevance of the identified genes through this integrative framework.

RESULTS: Consistent GMV reductions in AD were observed in the bilateral middle temporal gyrus, right superior temporal gyrus, and other key subcortical regions. The conjFDR analysis identified 20, 17, 78, 87, and 82 genes shared between AD-related GMV reductions and GLU, HbA1c, HDL-C, LDL-C, and TG, respectively. Notably, 6 genes were shared across all five metabolic markers. Enrichment analysis implicated these genes in biological processes related to Aβ aggregation and phosphatidylinositol metabolism.

CONCLUSIONS: This study reveals a convergent genetic architecture underlying AD-related GMV atrophy and metabolic dysfunction. These findings may offer novel insights into the molecular interplay between systemic metabolism and neurodegeneration in AD and highlight potential targets for therapeutic strategies.},
}

@article {pmid41478818,
year = {2026},
author = {Mummery, CJ and Li-Hsian, CC and Lasagna-Reeves, CA and Ossenkoppele, R and Rowe, CC and Scharre, DW and Wang, H and Kyaga, S and Cummings, JL},
title = {Tau in Alzheimer's disease: Shaping the future patient journey.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100447},
doi = {10.1016/j.tjpad.2025.100447},
pmid = {41478818},
issn = {2426-0266},
abstract = {Alzheimer's disease is a complex and multifactorial disease characterized by two key pathological hallmarks: amyloid-beta plaques and tau neurofibrillary tangles. Recent progress has led to the development and approval of disease-targeted therapies for Alzheimer's disease in the form of anti-amyloid-beta monoclonal antibodies. However, findings suggest that amelioration of multiple pathological drivers may be required to maximize clinical effect. An increasing body of evidence suggests that tau is a critical player in Alzheimer's disease pathophysiology, contributing significantly to neurodegeneration and cognitive decline. There are now several tau-targeting drugs in clinical development. In this review, we build on research and advancements in the field of tau to envision how an increasing focus on tau could shape the future Alzheimer's disease patient journey. We highlight the potential of tau as both a promising therapeutic target and a valuable biomarker, with the potential to inform treatment decisions and provide insight into disease trajectories. We also consider what a greater focus on tau may bring to an already evolving patient care pathway characterized by an increased influx of patients presenting earlier in the disease continuum, changes in workflow and infrastructural requirements, and increased complexity in treatment decision-making, treatment administration, treatment monitoring, and patient tracking. This review underscores the critical changes that may be required and knowledge gaps to be elucidated to ensure healthcare system preparedness for additional classes of disease-targeted therapy to move toward a next-generation, individualized treatment approach to Alzheimer's disease diagnosis and care.},
}

@article {pmid41478817,
year = {2026},
author = {Qi, L and Zheng, F and Tu, M and Abdullah, R and Zhao, Y and Su, X and Zhou, D and Peng, G},
title = {Safety profiles of lecanemab: A systematic review and meta-analysis of randomized controlled trials and real-world evidence.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100473},
doi = {10.1016/j.tjpad.2025.100473},
pmid = {41478817},
issn = {2426-0266},
abstract = {BACKGROUND: Safety profiles of lecanemab, an anti-amyloid-β antibody for the treatment of early Alzheimer's disease (AD), remain uncertain and may vary between randomized controlled trials (RCTs) and real-world evidence (RWE) studies.

OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the safety, tolerability, and acceptability of lecanemab based on findings from both RCTs and emerging RWE studies.

METHODS: We systematically searched major databases and clinical trial registries from their inception to June 2025. Random-effects meta-analyses were performed to estimate the pooled incidence of key safety outcomes, including amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation (due to ARIA, adverse events [AEs], or any cause). The risk of ARIA according to the ApoE4 genotype was assessed via relative risk (RR). This study was registered with PROSPERO (No. CRD420251110679).

RESULTS: A total of two RCTs and five RWE studies encompassing 1576 patients were included. The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%-34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis. The pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.

CONCLUSIONS: Lecanemab-related ARIA demonstrates a clear ApoE4 gene-dose effect, supporting routine ApoE4 genotyping before treatment. Standardizing pre-infusion prophylaxis may reduce variability in IRRs incidence, while prompt recognition and management of ARIA are critical for improving treatment tolerability. These findings provide important evidence to support the safe clinical use of lecanemab.},
}

@article {pmid41478541,
year = {2025},
author = {Zafar, I and Khan, MS and Jamal, A and Shafiq, S and Bahwerth, FS and Khan, NU},
title = {Precision therapeutic strategies for Alzheimer's disease: Amyloid β-targeted foundations and multimodal next-generation approaches.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104070},
doi = {10.1016/j.mcn.2025.104070},
pmid = {41478541},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and a significant unmet medical challenge, pathologically characterized by amyloid β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Although Aβ has long been a central therapeutic target, clinical translation has historically been hindered by late-stage intervention, inadequate blood-brain barrier (BBB) penetration, and the molecular heterogeneity of AD. Recent advances with Aβ-targeted monoclonal antibodies, particularly lecanemab and donanemab, have provided the first clinical evidence of disease modification, demonstrating robust amyloid clearance and measurable slowing of cognitive decline in early-stage AD. These results validate the Aβ hypothesis but also highlight persistent barriers, including amyloid-related imaging abnormalities (ARIA), questions about the durability of benefit, challenges in patient stratification, and the high economic burden of biologics. To overcome these limitations, next-generation strategies are emerging that extend beyond single-pathway targeting toward multimodal and precision-based frameworks. Innovative approaches include tau-directed therapies to prevent the propagation of neurofibrillary tangles, immunomodulatory strategies to enhance microglial clearance of aggregated proteins, and neuroprotective interventions to counteract oxidative and inflammatory stress. Concurrently, nanotechnology-based drug delivery systems are being engineered to efficiently traverse the BBB and deliver multifunctional payloads, while artificial intelligence (AI)- driven discovery platforms are accelerating target identification, biomarker integration, and patient stratification. Future perspectives emphasize the importance of preclinical-stage intervention, long-term efficacy trials, and the adoption of personalised treatment paradigms that integrate genomic, biomarker, and digital profiling to optimise outcomes. Collectively, these advances signal a paradigm shift in AD therapeutics, positioning Aβ-targeted therapies as a foundation while paving the way for combination strategies that more effectively address the disease's multifactorial nature.},
}

@article {pmid41478465,
year = {2025},
author = {Bandarupalli, T and Noonan, C and Hansen, K and Weaver, R and Baumann, K and Banks, WA and Erickson, MA and Rhea, EM},
title = {Acute peripheral versus central inhibition of insulin receptors differentially alters cytokine and blood-brain barrier responses to an inflammatory stimulus.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106251},
doi = {10.1016/j.bbi.2025.106251},
pmid = {41478465},
issn = {1090-2139},
abstract = {The blood-brain barrier (BBB)'s role in protecting the brain from exposure to harmful circulating factors has led to its disruption being implicated in neurodegenerative diseases such as vascular dementia and Alzheimer's disease. Insulin resistance, defined by an impaired response to insulin, is a common feature of metabolic disorders and neurodegenerative diseases. Importantly, individuals can possess peripheral insulin resistance independent of central insulin resistance and vice versa. States of insulin resistance, like diabetes mellitus for peripheral insulin resistance and Alzheimer's disease for central insulin resistance, are associated with inflammation and BBB disruption. However, the contributions of acute impairment of insulin receptor signaling solely in the periphery versus the brain to inflammation and BBB disruption are not clear. As central vs peripheral insulin resistance could have different effects on inflammation, we characterized the effects of acute central versus peripheral insulin receptor inhibition with or without an inflammatory insult, using lipopolysaccharide (LPS) as a prototypic immune stimulus. Male CD-1 mice were treated with an insulin receptor antagonist (S961), peripherally (intraperitoneal) or centrally (intranasal). This treatment was then followed by an intraperitoneal administration of either saline or LPS 30 min later, at a single 3 mg/kg dose known to cause inflammation and BBB disruption. Assays of BBB disruption and brain and serum collection were done 28 h after the injections. Metabolic hormones, cytokines, and the acute phase protein serum amyloid a (SAA) were then measured in serum and brain homogenates. In the absence of LPS, central S961 reduced serum hormones including ghrelin, gastric inhibitory peptide (GIP), and glucagon. Peripheral S961 significantly increased many cytokines in both brain and blood, whereas central S961 decreased serum SAA and increased a few cytokines. BBB integrity was not affected by S961 alone, but central S961 decreased LPS-induced BBB disruption and also lowered serum levels of SAA. These findings highlight the differential effects of peripheral versus central insulin receptor inhibition on cytokine responses and BBB integrity in the presence and absence of acute inflammation, elucidating differences in the molecular mechanisms for insulin receptor signaling depending on the location of signaling dysfunction. The results suggest a potential neuroprotective role of acute central insulin inhibition during acute inflammation.},
}

@article {pmid41478424,
year = {2025},
author = {Zhang, Y and Chen, L and Jin, J and Xin, Y and Wang, J and Zhang, A},
title = {Therapeutic application of fecal microbiota transplantation for neurological diseases: Exploring novel mechanisms and perspectives.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115631},
doi = {10.1016/j.expneurol.2025.115631},
pmid = {41478424},
issn = {1090-2430},
abstract = {Recently, fecal microbiota transplantation (FMT) has garnered widespread attention as an emerging therapeutic approach in the field of neurological disorders. In this study, we review the research progress of FMT in treating neurological disorders. First, the development, safety, and efficacy of FMT are introduced. Subsequently, the application and potential mechanisms of FMT in neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), neurodevelopmental disorders (such as autism spectrum disorder and attention deficit hyperactivity disorder), and other neurological conditions are elaborated in detail. Particularly, we explore the pivotal role of the microbiota-gut-brain axis in FMT for treating neurological disorders, as well as how FMT influences neurological function by regulating the gut microbiota and its metabolites, immune system and inflammatory responses, and neurotransmitters. However, FMT also faces numerous challenges in the treatment of neurological disorders, such as ethical issues, safety concerns, and standardization problems. Therefore, this review also prospects the future development directions of FMT in the treatment of neurological diseases, including personalized therapy and combination therapies. FMT may be a feasible and promising option for treating various neurological disorders, but a comprehensive understanding of its working principles and continuous improvement of its application in clinical practice are still ongoing.},
}

@article {pmid41477991,
year = {2025},
author = {Hu, H and Cheng, Q and Li, D and Li, Y and Li, X and Chen, Y and Guo, Y and Tian, S and Jiang, Y and Chen, Y and Liu, Y and Li, S},
title = {Ponicidin ameliorates Alzheimer's disease through dual inhibition of RIPK1-mediated neuroinflammation and necroptosis.},
journal = {International immunopharmacology},
volume = {171},
number = {},
pages = {116095},
doi = {10.1016/j.intimp.2025.116095},
pmid = {41477991},
issn = {1878-1705},
abstract = {Ponicidin (Pon), a diterpenoid isolated from Rabdosia rubescens, exhibits a broad range of pharmacological activities, including anti-inflammatory effects. However, its therapeutic potential in Alzheimer's disease (AD), particularly in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains underexplored. This study aims to investigate the mechanism through which Pon targets RIPK1 to alleviate AD pathogenesis. The interaction between Pon and RIPK1 was confirmed using bio-layer interferometry (BLI) and drug affinity responsive target stability (DARTS) assays. In vitro, the effects of Pon on inflammatory responses and necroptosis were evaluated in BV2 microglial cells (BV2 cells) and HT22 hippocampal neuronal cells (HT22 cells) using Enzyme-linked immunosorbent assay (ELISA), Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting (WB), and flow cytometry. In vivo, Pon's therapeutic efficacy was assessed in the 5 × FAD transgenic mouse model of AD through behavioral tests, histological analysis, and biochemical assays. Pon was found to bind RIPK1 with high affinity (KD = 135 nM) and enhance RIPK1's resistance to proteolytic degradation. In microglial cells, Pon effectively inhibited the release of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) by disrupting the RIPK1-janus kinase 1 (JAK1)-signal transducer and activator of transcription 1 (STAT1) signaling pathway. In neurons, Pon suppressed RIPK1-mediated necroptosis by blocking the RIPK1-RIPK3-mixed lineage kinase domain-like protein (MLKL) cascade. Behavioral analysis of 5 × FAD mice revealed that Pon treatment significantly improved cognitive function, reduced amyloid-beta (Aβ) plaque deposition, and alleviated neuroinflammation and necroptosis in the brain. Pon exerts dual neuroprotective effects by targeting RIPK1, mitigating both neuroinflammation and necroptosis, two critical pathological processes in AD. These findings underscore Pon's potential as a disease-modifying therapy for AD and provide a foundation for the clinical development of natural product-derived RIPK1 inhibitors in neurodegenerative diseases.},
}

@article {pmid41477911,
year = {2026},
author = {Yu, W and Zhuang, D and Wang, K and Qu, Y},
title = {JWX-A1223 attenuates cognitive deficits and tau protein hyperphosphorylation via the Akt/GSK3β pathway in APP/PS1 mice.},
journal = {Archives of physiology and biochemistry},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/13813455.2025.2610481},
pmid = {41477911},
issn = {1744-4160},
abstract = {BACKGOUND: Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, affecting memory, thinking, and behaviour. Its neuropathology includes amyloid plaques and neurofibrillary tangles in the brain.

MATERIALS: Amyloid plaques consist of misfolded beta-amyloid protein, while tangles are made of hyperphosphorylated tau protein.

METHOD: After treatment with JWX-A1223, the APP/PS1 mice showed significant cognitive improvement in the Morris water maze test. They had shorter escape latency, reduced swimming distance, and longer stay time in the target quadrant, indicating enhanced spatial learning and memory.

RESULTS: The treatment with JWX-A1223 also significantly reduced the phosphorylation levels of tau protein at Ser202, Ser396 and Ser404 sites in the cerebral cortex and hippocampus of mice, while increasing the phosphorylation levels at Ser473 site of Akt and Ser9 site of GSK3β.

CONSLUSION: It indicates that by regulating the activity of the Akt/GSK3β pathway, it alleviates the excessive phosphorylation of tau protein and thereby improves cognitive impairment.},
}

@article {pmid41477735,
year = {2026},
author = {Tsai, HR and Lin, YJ and Loh, CH and Lee, YC and Huang, HK},
title = {Risk of Alzheimer Disease and Related Dementia after Retinal Vascular Occlusion: A Nationwide Cohort Analysis.},
journal = {Ophthalmology. Retina},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.oret.2025.10.017},
pmid = {41477735},
issn = {2468-6530},
abstract = {PURPOSE: To evaluate the risk of developing Alzheimer disease (AD) and related dementia in patients with newly diagnosed retinal vascular occlusion.

DESIGN: A nationwide population-based cohort study using claims data from Taiwan's National Health Insurance Research Database (NHIRD).

PARTICIPANTS AND CONTROLS: A total of 39 540 individuals with diagnoses of retinal vascular occlusion between 2011 and 2019 in Taiwan and 395 400 age- and sex-matched nonretinal vascular occlusion individuals without prior diagnoses of any dementia.

METHODS: Patients with newly diagnosed retinal vascular occlusion were identified in the NHIRD, and baseline characteristics were collected. The study endpoints, including AD, vascular dementia (VD), and all-cause dementia, were determined by ≥2 separate outpatient diagnoses or a single discharge diagnosis. Inverse probability of treatment weighting (IPTW) was applied to balance baseline covariates and control potential confounders. Cox proportional hazards models were used to estimate the hazard ratio (HR) for each outcome.

MAIN OUTCOME MEASURES: Development of AD, VD, and all-cause dementia.

RESULTS: After IPTW, 38 522 patients with retinal vascular occlusion and 395 740 nonretinal vascular occlusion individuals were included. Patients with retinal vascular occlusion had increased risks of AD (HR, 1.57; 95% confidence interval [CI], 1.39-1.80), VD (HR, 1.76; 95% CI, 1.58-1.95), and all-cause dementia (HR, 1.58; 95% CI, 1.50-1.65). Both retinal artery occlusion and retinal vein occlusion were associated with increased risks of AD (HR, 1.59; 95% CI, 1.14-2.23; and HR, 1.58; 95% CI, 1.39-1.80, respectively), VD (HR, 1.79; 95% CI, 1.32-2.43; and HR, 1.77; 95% CI, 1.59-1.98, respectively), and all-cause dementia (HR, 1.62; 95% CI, 1.42-1.86; and HR, 1.58; 95% CI, 1.52-1.67, respectively).

CONCLUSIONS: Patients with retinal vascular occlusion had moderately increased risks of AD and related dementias. Therefore, monitoring for dementia symptoms in patients with retinal vascular occlusion may facilitate earlier detection and intervention.

FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.},
}

@article {pmid41477525,
year = {2025},
author = {Zheng, M and Hong, X and Liao, P and Huang, H and Zhang, Y and Xu, W and Li, H},
title = {Plant-Derived Exosome-Like Nanoparticles: A Promising Therapeutic for Neurological Disorders and Drug Delivery.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {15769-15791},
pmid = {41477525},
issn = {1178-2013},
mesh = {Humans ; *Exosomes/chemistry ; *Nanoparticles/chemistry ; Animals ; *Nervous System Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; *Drug Delivery Systems/methods ; *Plants/chemistry ; },
abstract = {Neurological disorders, including ischemic stroke, Alzheimer's disease, and Parkinson's disease, exhibit high incidence rates and pose significant health challenges. Current pharmacological treatments often fail to adequately address clinical needs due to obstacles such as limited penetration of the blood-brain barrier and suboptimal efficacy. Plant-derived exosome-like nanoparticles (PELNs) have emerged as promising therapeutic agents due to their superior biocompatibility, low toxicity, ability to traverse the blood-brain barrier, and abundance of lipids, microRNAs, and other bioactive compounds. This review provides a comprehensive overview of recent advancements in PELNs preparation technologies, elucidates the mechanisms of action of their principal bioactive components, and explores their therapeutic applications across various neurological disorders, thereby offering a theoretical foundation for the development of related treatment strategies. Nonetheless, researches on PELNs continue to encounter significant challenges. At the production level, there is an absence of standardized isolation protocols, and the yields remain inadequate to satisfy clinical requirements. Clinically, the efficacy in humans has yet to be established, and the available safety data are insufficient. Technically, the lack of standardized storage conditions and the susceptibility of biological stability to external factors further complicate the field. This review delineates these challenges to offer insights for advancing both fundamental research and the clinical translation of PELNs.},
}

Humans
*Exosomes/chemistry
*Nanoparticles/chemistry
Animals
*Nervous System Diseases/drug therapy
Blood-Brain Barrier/metabolism
*Drug Delivery Systems/methods
*Plants/chemistry

@article {pmid41477168,
year = {2025},
author = {Xiao, Y and Li, H and Han, X and Liu, Y and Sun, J and Sun, C and Wang, Y and Ye, T and Cheng, X},
title = {Qi-Fu-Yin ameliorates physiological frailty in male 5xFAD mice through remodeling the gut microbiota and modulating the cerebral cortex metabolism.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1622286},
pmid = {41477168},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease that can only be managed rather than cured, bringing a substantial burden to society. Frailty and cognition are intertwined in a cycle of decline, affecting the prognosis of AD. Qi-Fu-Yin (QFY) is a classic prescription in traditional Chinese medicine for dementia. While most studies have focused on cognitive impairment, research on physiological frailty remains relatively scarce in AD, especially in 5xFAD mice. We aimed to investigate the impacts of QFY on the physiological frailty of male 5xFAD mice.

METHODS: Male 5xFAD mice received QFY, followed by grip strength test, rotarod test, grading score of frailty, lipofuscin staining, SA-β-gal and Aβ co-staining. The metabolite alteration and the intestinal flora composition were analyzed by non-targeted metabolomics and 16S rRNA sequencing. Moreover, Spearman's correlation analysis was used to integrate behavioral results, differentially expressed metabolites, and altered bacterial genera.

RESULTS: We discovered that QFY improved grip strength, riding time, score of frailty, lipofuscin deposition, SA-β-gal, and Aβ in male 5xFAD mice. The results of untargeted metabolomics showed that metabolites such as proline, PS (18:1/18:0), and PFSA-CI were downregulated in the male 5xFAD mice compared with C57BJ/6JXSJL mice, while PE (18:1/18:1) was upregulated. QFY treatment reversed these changes, restoring metabolite levels toward those of C57BJ/6JXSJL mice. Arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and butyrate metabolism were filtered out as the important metabolic pathways between the C57BJ/6JXSJL mice and the male 5xFAD mice, as well as between the 5xFAD mice and the 5xFAD mice with QFY treatment. Moreover, Ruminococcaceae, Subdoligranulum, Bacteroides, Alistipes, Rikenellaceae_RC9_gut_group, and Odoribacter, which were lower in male 5xFAD mice, were improved after QFY intervention.

DISCUSSION: The differential intestinal flora might improve the metabolism of brain tissue as well as muscle strength and coordination through Short-chain fatty acids (SCFAs). The differential metabolites caused by QFY intervention also have an improving effect on physiological frailty. We suggest that QFY exerts protective impacts against the physiological frailty in AD by adjusting the muscle-gut-brain axis.},
}

@article {pmid41477167,
year = {2025},
author = {Garcia, ML and Denton, AR and Jackson, NL and Scofield, MD and McMahon, LL},
title = {Pharmacologically increasing O-GlcNAcylation increases complexity of astrocytes in the dentate gyrus of TgF344-AD rats.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1690410},
pmid = {41477167},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) pathology begins two or three decades prior to the onset of cognitive symptoms and is characterized by amyloid-β (Aβ) and hyperphosphorylated tau (pTau) accumulation, reactive glial cells, increased inflammation, and neuronal degeneration in later stages. Preclinical studies report that increasing the post-translational modification, O-GlcNAcylation, involving the addition of a single N-acetylglucosamine (GlcNAc) moiety to serine or threonine residues, can reduce amyloidogenic processing of amyloid precursor protein (APP) and compete with serine phosphorylation on tau, decreasing hyperphosphorylated tau accumulation. Protein O-GlcNAcylation can have anti-inflammatory effects, suggesting the possibility that increasing O-GlcNAcylation may decrease reactive gliosis and other pathological changes in AD.

METHODS: This study aimed to assess the possible beneficial effects of pharmacologically enhancing O-GlcNAcylation by inhibiting O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc moieties, on progressive AD pathology using female TgF344-AD rats. The selective OGA inhibitor thiamet-G [TMG; 10 mg/kg, subcutaneously (s.c.)] was administered three times per week for 3 months starting at 6 months of age, a time point when Aβ pathology is evident in the hippocampus. Western blot analysis was used to measure protein levels of GFAP, Iba-1, and Aβ. Immunohistochemistry and confocal imaging were used to assess Aβ plaques, astrocyte and microglia complexity, and degeneration of tyrosine hydroxylase-positive (TH+) axons.

RESULTS: In TgF344-AD rats, we found significantly increased astrocyte complexity, defined as increased process length and branches, increased numbers of microglia, loss of noradrenergic axons (NA), and significant Aβ plaques compared to WT, confirming previous work by us and others. Notably, pharmacologically increasing O-GlcNAcylation further increased astrocyte complexity in TgF344-AD rats, specifically those located in close proximity to Aβ plaques, while microglia morphology and Aβ staining were unaffected. O-GlcNAcylation was not able to lessen the loss of TH + axons in TgF344-AD rats, although fewer dystrophic axons were observed, suggesting a possible beneficial effect.

DISCUSSION: Our findings demonstrate that increasing O-GlcNAcylation in TgF344-AD rats using a cyclical treatment protocol at a time when Aβ pathology is already significant does not provide broad beneficial effects on Aβ accumulation, microglial reactivity, or noradrenergic axon loss, although there appears to be fewer dystrophic axons. Importantly, increasing O-GlcNAcylation in TgF344-AD rats has dual beneficial effects on astrocyte reactivity. Astrocytes in close proximity to Aβ plaques are more complex with longer processes and more branches compared to those in saline-treated TgF344-AD rats at the same distance, enabling them to surround plaques and protect nearby neurons. Astrocytes located at more distal locations from plaques are less reactive than those at the same distance in saline-treated TgF344-AD rats, permitting a less pathological local environment for nearby neurons. Our findings offer new insights into the possible mechanisms that might contribute to the beneficial therapeutic effects of increasing O-GlcNAcylation during progressive AD pathology.},
}

@article {pmid41476782,
year = {2025},
author = {Zhu, Y and Liu, H and He, M and Xu, Z and Sun, L and Wu, Z and Niu, X and Huang, S and Wang, J and Ran, X},
title = {Epidemiology and Risk Factors Characteristics of Alzheimer's Disease in Southwestern China: A Cross-Sectional Study.},
journal = {Clinical interventions in aging},
volume = {20},
number = {},
pages = {2685-2704},
pmid = {41476782},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/epidemiology ; China/epidemiology ; Female ; Male ; Risk Factors ; Aged ; *Cognitive Dysfunction/epidemiology ; Cross-Sectional Studies ; Aged, 80 and over ; Middle Aged ; Prevalence ; Rural Population ; Sex Factors ; Age Factors ; Educational Status ; Comorbidity ; Logistic Models ; },
abstract = {BACKGROUND: To address the regional heterogeneity of Alzheimer's disease, a large-scale epidemiological study of 12,421 elderly individuals was conducted in southwestern China to depict its unique risk characteristics.

METHODS: A total of 12,421 subjects were selected via cluster sampling from southwestern China after low quality data were filtered out. On the basis of investigations and medical imaging examinations, three groups were distinguished: the AD, mild cognitive impairment (MCI), and normal control groups. The risk factors for AD and MCI were analysed via a multivariate logistic regression model.

RESULTS: This study identifies a high burden of cognitive impairment in southwestern China, with 22.07% of adults aged ≥60 years exhibiting cognitive decline and 5.81% diagnosed with Alzheimer's disease rates surpassing national and global averages. Key risk factors included age >80 years, female sex, low education, rural residence, surgical history, and urological comorbidities. These findings underscore the need for region-specific prevention strategies, prioritizing older, less-educated rural women through combined cognitive and vascular interventions, while integrating cognitive screening into primary care in underserved areas for early detection and intervention.

CONCLUSION: Elderly individuals in southwestern China exhibit a high prevalence of cognitive impairment, with AD associated with complex risk factors including established contributors like advanced age, dementia family history, alcohol abuse, and multisystem comorbidities-while notably identifying surgical history and urolithiasis as region specific risk signals. These findings underscore regional, environmental, and ethnic influences on AD pathogenesis, requiring tailored prevention/treatment. Future priorities include integrating brief cognitive screening into primary care, targeting high-risk groups (eg, undereducated rural elderly women), and establishing prospective cohorts to clarify causal links between urolithiasis, surgical history, and cognitive decline for refined region-adapted AD prevention.},
}

Humans
*Alzheimer Disease/epidemiology
China/epidemiology
Female
Male
Risk Factors
Aged
*Cognitive Dysfunction/epidemiology
Cross-Sectional Studies
Aged, 80 and over
Middle Aged
Prevalence
Rural Population
Sex Factors
Age Factors
Educational Status
Comorbidity
Logistic Models

@article {pmid41476179,
year = {2025},
author = {Taheri, E and Raeeszadeh-Sarmazdeh, M},
title = {Evaluating the effect of minimal TIMP variants on protecting and transport across the rat brain microvascular cells (RBMEC).},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30643-9},
pmid = {41476179},
issn = {2045-2322},
abstract = {Tissue inhibitors of metalloproteinases (TIMPs), endogenous inhibitors of matrix metalloproteinases (MMPs), can be tailored to regulate MMP activity and mitigate the disruptive effects of specific MMPs when dysregulated in diseases. MMPs, especially MMP-9, are major contributors to the degradation of extracellular matrix components, leading to BBB disruption in neurological disorders. The upregulation of MMPs undermines blood-brain barrier (BBB) integrity and drives neuroinflammation. Engineering minimal protein variants offers enhanced modularity, tissue penetration, and BBB permeability. Minimal TIMP variants were engineered, aiming to improve their therapeutic reach across both sides of the BBB, particularly when delivery to the brain is essential. In this study, we assessed the protective effects of mTC1 and mTC3 on BBB integrity using an in vitro model of rat brain microvascular endothelial cells (RBMECs). Barrier function was evaluated following treatment with recombinant MMP-9, either alone or co-treated with native TIMP-1, TIMP-3, or the engineered minimal variants. MMP-9 induced a dose-dependent increase in BBB permeability, reflected by a decrease in trans-endothelial electrical resistance (TEER) and increased paracellular transport of fluorescent tracers. Co-treatment with TIMP-1, TIMP-3, mTC1, or mTC3 significantly attenuated MMP-9-mediated disruption of tight junctions of RBMECs, preserving TEER values and reducing permeability. Immunofluorescence staining for tight junction proteins, ZO-1 and occludin, further validated the preservation of endothelial integrity in the presence of wild-type human TIMPs and engineered TIMP variants. These findings underscore the potential of engineered minimal TIMPs as molecular tools to stabilize the BBB and support their future application in mechanistic studies focused on BBB protection.},
}

@article {pmid41476028,
year = {2026},
author = {Zhang, W and Liu, H and Zhang, C and Li, Y and Fang, K and Zhou, Y and Weng, L and Fang, L and Luo, Y and Xiao, H and Zhou, L and Jiao, B and Shen, L},
title = {Six-month follow-up of ARIA-H and iron deposition in real-world lecanemab therapy for Alzheimer's disease: Evidence from a Chinese 7T MRI cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {1},
pages = {e71044},
doi = {10.1002/alz.71044},
pmid = {41476028},
issn = {1552-5279},
support = {U22A20300 82371434//National Natural Science Foundation of China/ ; 2021ZD0201803//STI2030-Major Projects/ ; 2023YFC3603700//the National Key R&D Program of China/ ; 2024JJ2097//the Outstanding Youth Fund of Hunan Provincial Natural Science Foundation/ ; 2024PT5108//the Scientific Research Program of FuRong Laboratory/ ; SMIDF-150-2025A19//the Brain Health Youth Fund of Shanghai Medical Innovation & Development Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Magnetic Resonance Imaging/methods ; Male ; Female ; *Iron/metabolism ; Aged ; Amyloid beta-Peptides/blood ; Follow-Up Studies ; Biomarkers/blood ; *Brain/diagnostic imaging/metabolism/drug effects ; tau Proteins/blood ; Cohort Studies ; China ; Middle Aged ; Peptide Fragments/blood ; East Asian People ; },
abstract = {INTRODUCTION: With the approval of lecanemab for treating Alzheimer's disease (AD), there is an urgent need to evaluate its safety and treatment effects on biomarkers in real-world practice.

METHODS: Patients receiving lecanemab (n = 72) underwent routine 3T and 7T magnetic resonance imaging (MRI) for amyloid-related imaging abnormality (ARIA) monitoring. Longitudinal changes of iron deposition assessed by quantitative susceptibility mapping (QSM) and its association with plasma biomarkers were further evaluated.

RESULTS: With use of 7T MRI, we identified characteristic perivascular features and detected ARIA with hemorrhages/hemosiderin deposition (ARIA-H) ≈4 months earlier than with 3T. QSM detected post-treatment regional susceptibility reductions. Decreased susceptibility in the temporal, frontal lobes, and the thalamus was associated with plasma amyloid beta 42 (Aβ42) and tau phosphorylated at threonine 217 (p-tau217) changes.

DISCUSSION: 7T MRI provides superior ARIA-H detection and iron dynamics monitoring, supporting its role in risk stratification and therapy assessment for lecanemab-treated patients. Iron deposition measured by QSM may serve as a promising neuroimaging marker for amyloid-targeting treatments.

HIGHLIGHTS: Using 7T magnetic resonance imaging (MRI), this study for the first time visualized amyloid-related imaging abnormality with hemorrhages/hemosiderin deposition (ARIA-H) at a submillimeter resolution, characterized by aggregated, clustered cerebral microbleeds in a perivascular distribution, suggesting overlapping pathology with cerebral amyloid angiopathy. The susceptibility-weighted imaging sequence on 7T MRI enabled detection of ARIA-H up to 4 months earlier. Plasma amyloid beta 42 (Aβ42) and tau phosphorylated at threonine 217 (p-tau 217) levels are sensitive biomarkers for amyloid targeted therapy. Quantitative susceptibility mapping (QSM) analysis demonstrated reduced cortical iron burden post-treatment, which has significant associations with plasma Aβ42 and p-tau 217 levels, highlighting QSM-derived iron quantification as a promising neuroimaging indicator for amyloid-targeted therapeutics.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Magnetic Resonance Imaging/methods
Male
Female
*Iron/metabolism
Aged
Amyloid beta-Peptides/blood
Follow-Up Studies
Biomarkers/blood
*Brain/diagnostic imaging/metabolism/drug effects
tau Proteins/blood
Cohort Studies
China
Middle Aged
Peptide Fragments/blood
East Asian People

@article {pmid41475761,
year = {2026},
author = {Mei, J and Shi, X and Chen, M and Li, Z and Cui, Y and Fang, C and Wu, X and Chen, X and Zeng, K and Yang, L},
title = {Chitosan/selenium nanoparticles Pickering emulsion prolong quercetin retention time to ameliorates cognitive disorder: Focus on restoring the metabolic disorder and gut microbiota.},
journal = {Carbohydrate polymers},
volume = {375},
number = {},
pages = {124804},
doi = {10.1016/j.carbpol.2025.124804},
pmid = {41475761},
issn = {1879-1344},
mesh = {*Quercetin/chemistry/pharmacology/administration & dosage/pharmacokinetics ; Animals ; *Gastrointestinal Microbiome/drug effects ; *Chitosan/chemistry ; Emulsions/chemistry ; *Nanoparticles/chemistry ; *Selenium/chemistry ; Mice ; Male ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy ; Brain/metabolism/drug effects ; },
abstract = {Gut microbiota influence brain inflammation and cognitive impairment by regulating lipid metabolism. The therapeutic efficacy of quercetin (Que) in Alzheimer's disease (AD) treatment is significantly limited by its poor water solubility and short residence time in vivo. Herein, Chitosan (CS) modified selenium nanoparticles was used to prepare a high-loading Pickering emulsion (Que-CS/Se-PE), improving bioaccessibility of Que. Simulated gastrointestinal fluid experiments demonstrate that Que-CS/Se-PE exhibits strong stability under acidic conditions. In vitro digestion studies indicate that Que-CS/Se-PE enables QUE to target intestinal fluids and release slowly. In vivo imaging revealed that the gastrointestinal retention time of Que-CS/Se-PE was up to 48 h. In HFD + D-gal-induced mice, Que-CS/Se-PE treatment reduced serum TC and brain TNF-α levels by 40.8 % and 31.5 %, respectively, indicating substantial improvement in lipid metabolism and neuroinflammation. Behavioral tests showed that Que-CS/Se-PE improved cognitive performance, with preference index elevated by 2.1-fold. Moreover, the relative abundances of Akkermansia, Lactobacillus, and Bacteroidota increased by 2.7-, 17.8-, and 4.7-fold, respectively. In conclusion, Que-CS/Se-PE exhibits interfacial stability, excellent adhesion, and sustained-release properties, significantly prolonging the retention time of quercetin in vivo and enhancing its bioavailability. Furthermore, it modulates lipid metabolism and gut microbiota, and finally ameliorates cognitive impairment in obesity and age-related AD.},
}

*Quercetin/chemistry/pharmacology/administration & dosage/pharmacokinetics
Animals
*Gastrointestinal Microbiome/drug effects
*Chitosan/chemistry
Emulsions/chemistry
*Nanoparticles/chemistry
*Selenium/chemistry
Mice
Male
Mice, Inbred C57BL
*Cognitive Dysfunction/drug therapy
Brain/metabolism/drug effects

@article {pmid41474058,
year = {2026},
author = {Naftchi-Ardebili, K and Singh, K and Popelka, GR and Pauly, KB},
title = {A deep-learning model for one-shot transcranial ultrasound simulation and phase aberration correction.},
journal = {Medical physics},
volume = {53},
number = {1},
pages = {e70259},
doi = {10.1002/mp.70259},
pmid = {41474058},
issn = {2473-4209},
support = {R01 Grant EB032743//National Science Foundation/ ; },
mesh = {*Deep Learning ; Humans ; *Image Processing, Computer-Assisted/methods ; Skull/diagnostic imaging ; Ultrasonography ; Tomography, X-Ray Computed ; },
abstract = {BACKGROUND: Transcranial ultrasound is a promising non-invasive neuromodulation technique with applications, including neuronal activity modulation, blood-brain barrier opening, targeted drug delivery, and thermal ablation. Its ability to deliver focused ultrasound waves to precise brain regions has led to over 50 clinical trials targeting conditions such as opioid addiction, Alzheimer's disease, dementia, epilepsy, and glioblastoma. However, skull heterogeneity complicates accurate focal spot prediction and energy delivery, requiring rapid yet precise phase aberration correction in clinical workflows.

PURPOSE: To address the trade-off between computational efficiency and accuracy in current focus prediction methods, we introduce TUSNet, a deep learning framework for rapid and accurate transcranial ultrasound pressure field and phase aberration correction computation.

METHODS: TUSNet, an end-to-end neural network, was trained to predict both 2D transcranial ultrasound pressure fields and phase corrections. TUSNet was trained on 180432 synthetic skull Computed Tomography (CT) segments, and tested on 1232 real skull CT segments. Its performance was benchmarked against k-Wave, a MATLAB-based acoustic simulation package, evaluating computation speed, focal spot accuracy, phase correction accuracy, and pressure magnitude estimation.

RESULTS: TUSNet computed pressure fields and phase corrections in 21 ms, which is over 1200 × $\times$ faster than k-Wave, while achieving 98.3% accuracy in peak pressure magnitude estimation and a mean focal positioning error of only 0.18 mm relative to k-Wave ground truth. End-to-end training took approximately 8 h on 4x NVIDIA A100 80 GB GPUs.

CONCLUSIONS: TUSNet demonstrates that deep learning can provide accurate and rapid estimates of phase aberrations and transcranial pressure fields, offering a promising direction for accelerating ultrasound treatment planning. While the present validation is based on simulated, noise-free ultrasound fields, the results establish a foundation that future experimental studies can build on to assess performance under real-world clinical conditions.},
}

*Deep Learning
Humans
*Image Processing, Computer-Assisted/methods
Skull/diagnostic imaging
Ultrasonography
Tomography, X-Ray Computed

@article {pmid41473419,
year = {2026},
author = {Tonegawa-Kuji, R and Karavani, E and Danziger, M and Zhang, P and Hou, Y and Zhou, Y and Bykova, M and Pieper, AA and Rosen-Zvi, M and Cummings, J and Cheng, F},
title = {Critical evaluation of real-world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {1},
pages = {e70193},
pmid = {41473419},
issn = {2352-8737},
abstract = {INTRODUCTION: Repurposing Food and Drug Administration (FDA)-approved drugs could accelerate treatment development for Alzheimer's disease (AD).

METHODS: Using the MarketScan claims database (2011 to 2020), we applied a trial emulation approach in two base cohorts: (1) individuals with mild cognitive impairment (MCI cohort) and (2) individuals aged ≥70 years (over-70 cohort). We evaluated drugs represented in clinical trials for AD, comparing them with same-class or active comparators. Covariate-adjusted hazard ratios (HRs) were estimated using inverse-probability-weighted Cox models.

RESULTS: A total of 6 out of 38 (16%) drugs in the MCI cohort and 10 out of 53 (19%) drugs in the over-70 cohort were associated with a lower AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion (vs escitalopram; HR 0.57, 95% confidence interval [CI] [0.49, 0.66]), trazodone (vs sertraline; HR 0.82, 95% CI [0.74, 0.91]), venlafaxine (vs escitalopram; 0.72, 95% CI [0.62, 0.84]), and zolpidem (vs lorazepam; HR 0.69, 95% CI [0.56, 0.85]) were associated with a lower AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort (vs metformin; HR 0.74, 95% CI [0.59, 0.93]).

DISCUSSION: This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Findings may inform future trial designs.

HIGHLIGHTS: Repurposing FDA-approved drugs originally developed for other diseases could accelerate treatment development for AD.We identified repurposable drugs that are in current or complete clinical trials of AD and emulated trials for these agents using a large-scale insurance claims-based database.Among 54 drugs evaluated, 6/38 (16%) drugs in the MCI cohort and 10/53 (19%) in the over-70 cohort were associated with reduced AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion, trazodone, venlafaxine, and zolpidem were associated with reduced AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort.A minority of repurposed table drugs that are in current or completed clinical trials for AD and meet criteria for inclusion in this study showed no effect in our trial emulation studies.This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Building on our findings, integrating real-world evidence can inform future trials and accelerate drug development for AD.},
}

@article {pmid41473323,
year = {2025},
author = {Salian, VS and Veerareddy, V and Tang, X and Xiao, Y and Kalari, KR and Kashyap, PC and Kandimalla, KK},
title = {Molecular Mechanisms Underlying the Regulation of VCAM-1 Expression by the Short-Chain Fatty Acid Butyrate.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.15.694447},
pmid = {41473323},
issn = {2692-8205},
abstract = {Over the past decade, cerebrovascular inflammation has been increasingly recognized as a contributor to the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD). One of the molecular hallmarks of cerebrovascular inflammation is the increased expression of vascular cell adhesion molecule (VCAM)-1 on blood-brain barrier (BBB) endothelial cells. Exposure to amyloid beta (Aβ) peptides, one of the primary hallmarks of AD, and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) induces VCAM-1 expression on the BBB endothelium, which facilitates extravasation of leukocytes into the brain thereby promoting an inflammatory response. Therefore, it is crucial to explore therapeutic agents that can inhibit VCAM-1 expression induced by Aβ and TNF-α. Short-chain fatty acids, such as butyrate, produced by the gut microbiota as byproducts of dietary fiber metabolism, are recognized for their anti-inflammatory properties. In this study, we successfully tested the hypothesis that butyrate mitigates Aβ and TNF-α-induced VCAM-1 expression in polarized human cerebral microvascular endothelial cell monolayers, a widely used BBB in vitro model. Our findings indicated that pre-treatment with butyrate significantly reduced Aβ42 and TNF-α mediated upregulation of VCAM-1. Furthermore, we have shown STAT3/GATA6 axis as a key mediator of anti-inflammatory effects of butyrate. These findings provide mechanistic insight into butyrate's protective role and highlight its potential to mitigate Aβ and TNF-α-induced cerebrovascular inflammation in AD.},
}

@article {pmid41473097,
year = {2025},
author = {Kang, MH and Kang, MA and Jeon, HJ and Shin, HC and Moon, H and Lee, DG and Park, HM},
title = {Evaluation of the safety and efficacy of a donepezil depot injection in dogs with canine cognitive dysfunction.},
journal = {Frontiers in veterinary science},
volume = {12},
number = {},
pages = {1724060},
pmid = {41473097},
issn = {2297-1769},
abstract = {Canine cognitive dysfunction (CCD) is an age-related neurodegenerative disorder for which effective treatments remain limited, and objective diagnostic and therapeutic assessment tools using biomarkers or neuroimaging are still lacking compared with human Alzheimer's disease. This study evaluated the safety and efficacy of a long-acting donepezil depot injection in dogs with CCD, using behavioral scores and serum neurofilament light chain (NfL) as primary outcomes, with baseline MRI for diagnostic support. Thirty-two dogs with clinically diagnosed CCD were randomly assigned to a high-dose group (n = 11), a low-dose group (n = 11), or a control group (n = 10). Diagnosis was established based on the Canine Cognitive Dysfunction Rating Scale (CCDR), the CAnine DEmentia Scale (CADES), and DISHAA scoring, and baseline MRI was performed in selected dogs with owner consent. A single intramuscular injection of donepezil depot was administered on day 0, and evaluations were conducted on days 14 and 28. The high-dose group showed significant improvements in CCDR, CADES, and DISHAA at both 14 and 28 days, whereas the low-dose group improved primarily at day 28, with earlier effects limited to CADES (p < 0.05). At day 28, both treatment groups had significantly lower serum NfL levels than controls (p < 0.05), while within-group values remained stable. Quality-of-life scores improved in activity, sociability, overall condition, and global QoL. Adverse events were mild and transient. These findings suggest that a single intramuscular injection of long-acting donepezil depot demonstrates favorable safety and potential efficacy in dogs with CCD, with improvements in behavioral scores and NfL supporting its therapeutic potential and highlighting the value of integrating clinical and biomarker-based assessments in future CCD management.},
}

@article {pmid41471864,
year = {2025},
author = {Cao, S and Shi, X and Chen, Y and Liu, T and Hu, J and Dong, X and Chen, H and Dai, J and Yin, H},
title = {Gut Microbiota-Targeted Photobiomodulation Ameliorates Alzheimer's Pathology via the Gut-Brain Axis: Comparable Efficacy to Transcranial Irradiation.},
journal = {Microorganisms},
volume = {13},
number = {12},
pages = {},
pmid = {41471864},
issn = {2076-2607},
support = {62175261//National Natural Science Foundation of China/ ; 2023YFB3609103//National Key R&D Program of China/ ; 2021-I2M-1-058//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 24JCZDJC00240//Natural Science Foundation of Tianjin/ ; },
abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with limited effective and affordable therapies. Photobiomodulation (PBM) offers a safe, non-invasive treatment strategy, yet conventional transcranial PBM (tc-PBM) is restricted by low skull penetration. To overcome this limitation, gut microbiota-targeted PBM (gm-PBM) has been proposed to modulate the gut-brain axis, though its efficacy and mechanisms remain unclear. Here, six-month-old APPswe/PS1dE9 mice received gm-PBM or tc-PBM (810 nm, 25 mW/cm[2], 20 min/day for 4 weeks). Behavioral testing revealed that both treatments improved spatial learning and memory, while histological analyses showed reduced amyloid-β deposition and microglial shift toward an anti-inflammatory phenotype. Notably, gm-PBM specifically enriched short-chain fatty acid-producing bacteria, elevated propionate, butyrate, and secondary bile acids, and restored intestinal barrier integrity, whereas tc-PBM induced minimal microbiota changes. These findings suggest that gm-PBM confers neuroprotective effects comparable to or exceeding tc-PBM through modulation of the gut microbiota-metabolism-immune axis, highlighting its potential as a non-invasive and cost-effective therapeutic approach for AD.},
}

@article {pmid41471351,
year = {2025},
author = {Makhaeva, GF and Utepova, IA and Rudakova, EV and Kovaleva, NV and Boltneva, NP and Zyryanova, EY and Musikhina, AA and Lazarev, VF and Vladimirova, SA and Guzhova, IV and Ganebnykh, IN and Astakhova, TY and Timokhina, EN and Chupakhin, ON and Charushin, VN and Richardson, RJ},
title = {1-Azinyl-1'-Alkenylferrocenes with Anticholinesterase, Antioxidant, and Antiaggregating Activities as Multifunctional Agents for Potential Treatment of Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {12},
pages = {},
doi = {10.3390/ph18121862},
pmid = {41471351},
issn = {1424-8247},
support = {24-63-00016//Russian Science Foundation/ ; },
abstract = {Background/Objectives: This study focused on synthesizing novel alkenyl derivatives of azinylferrocenes and evaluating their potential as Alzheimer's disease (AD) therapeutics. Methods: 1-Azinyl-1'-acetylferrocenes were obtained by regioselective acetylation of azinylferrocenes, followed by the Wittig reaction or reduction of 1-azinyl-1'-acetylferrocenes and subsequent dehydration of the resulting alcohols. The synthesized compounds underwent the following biological activity testing relevant to AD: inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and off-target carboxylesterase (CES); antioxidant capacity (ABTS and FRAP assays); inhibition of Aβ42 self-aggregation (thioflavin method); blocking AChE-induced β-amyloid aggregation (propidium displacement); and cytotoxicity in SH-SY5Y and MSC-Neu cells (MTT assay). Results: Quinoline and bipyridine derivatives demonstrated effective cholinesterase inhibition, especially quinoline 7b (AChE IC50 3.32 μM; BChE IC50 3.68 μM), while acridine derivatives were poor inhibitors. Quantum chemical (QC) calculations predicted that acridine derivatives were especially prone to form stable dimers. Molecular docking into protein targets generated by an AlphaFold3 reproduction code showed that these dimers were too bulky to access enzyme active sites, yet they could bind to protein surfaces to inhibit Aβ42 self-aggregation and displace propidium from the AChE peripheral anionic site. All compounds showed high antioxidant activity in ABTS and FRAP assays, with quinoline derivatives being 2-4 times more potent than Trolox. QC calculations supported these findings. Quinoline and bipyridine derivatives also exhibited low cytotoxicity and scant CES inhibition. Conclusions: Overall, the synthesized ferrocenes, particularly the quinoline and bipyridine derivatives, appear promising for further research as multifunctional therapeutic agents targeting AD due to their anticholinesterase, antiaggregating, and antioxidant activities combined with low toxicity.},
}

@article {pmid41471079,
year = {2025},
author = {Trasca, DM and Dorin, PI and Carmen, S and Varut, RM and Singer, CE and Radivojevic, K and Stoica, GA},
title = {Artificial Intelligence in Biomedicine: A Systematic Review from Nanomedicine to Neurology and Hepatology.},
journal = {Pharmaceutics},
volume = {17},
number = {12},
pages = {},
doi = {10.3390/pharmaceutics17121564},
pmid = {41471079},
issn = {1999-4923},
abstract = {Background/Objectives: This review evaluates the expanding contributions of artificial intelligence (AI) across biomedicine, focusing on cancer therapy and nanomedicine, cardiology and medical imaging, neurodegenerative disorders, and liver disease. Core AI concepts (machine learning, deep learning, artificial neural networks, model training/validation, and explainability) are introduced to frame application domains. Methods: A systematic search of major biomedical databases (2010-2025) identified English-language original studies on AI in these four areas; 203 articles meeting PRISMA 2020 criteria were included in a qualitative synthesis. Results: In oncology and nanomedicine, AI-driven methods expedite nanocarrier design, predict biodistribution and treatment response, and enable nanoparticle-enhanced monitoring. In cardiology, algorithms enhance ECG interpretation, coronary calcium scoring, automated image segmentation, and noninvasive FFR estimation. For neurological disease, multimodal AI models integrate imaging and biomarker data to improve early detection and patient stratification. In hepatology, AI supports digital histopathology, augments intraoperative robotics, and refines transplant wait-list prioritization. Common obstacles are highlighted, including data heterogeneity, lack of standardized acquisition protocols, model transparency, and the scarcity of prospective multicenter validation. Conclusions: AI is emerging as a practical enabler across these biomedical fields, but its safe and equitable use requires harmonized data, rigorous multicentre validation, and more transparent models to ensure clinical benefit while minimizing bias.},
}

@article {pmid41471033,
year = {2025},
author = {Park, YC and Seol, E and Lee, J and Hong, JH and Jung, JG and Sunwoo, J},
title = {Pharmacokinetic Evaluation of GB-5001, a Long-Acting Injectable Formulation of Donepezil, in Healthy Korean Participants: Population Pharmacokinetics with Phase 1 Study.},
journal = {Pharmaceutics},
volume = {17},
number = {12},
pages = {},
doi = {10.3390/pharmaceutics17121517},
pmid = {41471033},
issn = {1999-4923},
support = {Not applicable//G2GBIO Inc./ ; },
abstract = {Background/Objectives: Oral donepezil, an acetylcholinesterase (AChE) inhibitor for Alzheimer's disease, faces adherence challenges. Long-acting injectable (LAI) formulations like GB-5001 aim to enhance adherence by reducing dosing frequency. This Phase 1, open-label, active-controlled, dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GB-5001 in healthy male adults. Methods: Participants were assigned to cohorts receiving GB-5001A or GB-5001D (LAI formulations) via intramuscular (IM) or subcutaneous (SC) injection, or oral Aricept[®]. Safety, PK, and PD (AChE inhibition) were assessed. The influence of CYP2D6 phenotype was explored, and modeling/simulation was performed. Results: Fifty healthy male participants completed the study. After IM administration, GB-5001A (70 mg, 140 mg, 280 mg) showed dose-dependent increases in exposure (AUCinf and Cmax), resulting in significantly extended exposure compared to oral Aricept[®] 10 mg. No serious adverse events were reported; the most common AEs were mild injection site reactions, which occurred in all treatment groups except the GB-5001A IM 70 mg group and the Aricept group. GB-5001A also demonstrated sustained AChE inhibition. Conclusions: GB-5001A, an LAI donepezil, showed favorable safety, dose-proportional PK, and sustained plasma exposure. It achieved a 3-4-fold longer half-life than oral donepezil. These findings, supported by modeling, highlight GB-5001A's potential as a once-monthly IM alternative for Alzheimer's disease treatment.},
}

@article {pmid41413577,
year = {2025},
author = {Chu, C and Wang, Y and Ma, L and Ouyang, Y and Zisis, G and Masters, CL and Goudey, B and Jin, L and Pan, Y and , },
title = {Development and validation of an interpretable clinical scoring model to monitor the progression of preclinical Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {268},
pmid = {41413577},
issn = {1758-9193},
support = {GNT2007912//National Health and Medical Research Council/ ; 23AARF-1020292/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Monitoring the progression of preclinical Alzheimer's disease (AD) is challenging due to the absence of obvious cognitive impairment, yet it's crucial for determining the optimal timing for disease-modifying treatments.

METHODS: This prognostic study used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study. The development cohort included 412 participants from the placebo arm, and external validation was performed using 342 participants from the treatment arm. All participants had baseline brain amyloid-beta (Aβ) positron emission tomography (PET) standardized uptake value ratios (SUVR) below 1.4. Using the AutoScore machine learning framework, we developed two interpretable models: the AutoScore Amyloid-Beta (ASAB) model to predict Aβ accumulation (> 1.4 SUVR) and the AutoScore Phosphorylated Tau (ASPT) model to predict plasma phosphorylated tau-217 (pTau-217) elevation (> 0.3 pg/mL) over 4.5 years. Model performance was assessed using the area under the receiver operating characteristic curve (AUC-ROC) with 95% confidence intervals (CIs).

RESULTS: The ASAB model achieved an AUC-ROC of 0.87 (95% CI, 0.79–0.95), and the ASPT model achieved 0.86 (95% CI, 0.78–0.94). Modified models excluding baseline Aβ SUVR or pTau-217 values maintained a strong performance (AUC-ROC 0.76–0.82). External validation demonstrated a robust performance, with an AUC-ROC of 0.83 (95% CI, 0.78–0.87) for ASAB and 0.84 (95% CI, 0.80–0.89) for ASPT. Key predictors included baseline biomarker levels, cholesterol, platelet count, alanine transaminase, and creatine kinase.

CONCLUSIONS: The AutoScore-based models accurately predict longitudinal Aβ and pTau-217 levels using readily available clinical and laboratory data. These interpretable tools could help clinicians and researchers monitor preclinical AD progression and identify optimal windows for intervention.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01931-3.},
}

@article {pmid41287056,
year = {2025},
author = {Gouilly, D and Da-Costa, A and Vrillon, A and Pistono, A and Goubeaud, M and Bertrand, E and Germain, J and Ainaoui, N and Bras, S and Catala, H and Planton, M and Lemesle, B and Hitzel, A and Salabert, AS and Nogueira, L and Mouton-Liger, F and Méligne, D and Jasse, L and Rafiq, M and Sarton, B and Silva, S and Alam, J and Paquet, C and Tauber, C and Thalamas, C and Payoux, P and Péran, P and Pariente, J},
title = {Inhibition of p38α MAPK increases short-term astrocyte reactivity: the exploratory VIP trial in early Alzheimer's disease.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {298},
pmid = {41287056},
issn = {1742-2094},
abstract = {BACKGROUND: Neuro-inflammation is an early mechanistic target in Alzheimer’s disease (AD). However, the effect of anti-inflammatory drugs on biomarkers of neuro-inflammation has yet to be described. Biomarkers of neuro-inflammation showed distinct evolution over the course of AD, suggesting that anti-inflammatory interventions could be beneficial or interfere with mechanisms of immune defense.

METHODS: We conducted a pilot and exploratory phase II trial to evaluate the short-term effects of neflamapimod, a drug known to inhibit the neuro-toxic pro-inflammatory properties of the p38α MAPK. Participants with early AD were randomized to receive neflamapimod 40 mg (n = 17) or placebo (n = 16) twice-daily for 12 weeks. The primary endpoint was the treatment-related change in PET imaging of the translocator protein (TSPO) using [18F]-DPA-714. The main secondary endpoints were cerebrospinal fluid (CSF) markers of microglial and astrocyte reactivity. We hypothesized that neuro-inflammation would be reduced at three months in PET and in CSF markers.

RESULTS: Neuro-inflammation was not reduced between the neflamapimod and placebo groups, and no change was observed in [18F]-DPA-714 PET. However, neflamapimod induced a significant increase in CSF GFAP levels compared to placebo. Multivariate analyses based on CSF biomarkers highlighted the contribution of sTREM2 in the pattern of variation that discriminated the two groups (accuracy = 71%). Patients who received neflamapimod and had baseline sTREM2 level above the median had the highest increase in GFAP compared to placebo, suggesting that neflamapimod may exacerbate reactive astrogliosis as a function of the TREM2-related microglial state. Safety analysis showed that three cases of CSF pleocytosis occurred during follow-up in participants receiving neflamapimod.

CONCLUSIONS: Neflamapimod at a dose of 40 mg twice-daily interfered with mechanisms of immune defense in early AD. Although this study is exploratory, our results may provide an explanation for the failure of previous anti-inflammatory interventions in early AD. Biomarkers of neuro-inflammation should be required in the next-generation trials targeting neuro-immune mechanisms in AD.

REGISTRY: ClinicalTrials.gov, Clinical Trial registration number: NCT03435861.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03625-x.},
}

@article {pmid41275266,
year = {2025},
author = {Roach, JC and Glusman, G and Rapozo, MK and Merrill, DA and Bramen, J and Hodes, JF and Siddarth, P and Meysami, S and Elhelou, SHK and Glatt, RM and Edens, L and Funk, C and Kelly, D and Shankle, WR and Bredesen, D and Raji, CA and Hood, L},
title = {Multidomain therapy for Alzheimer's disease: a scoping review of cognitive decline trials.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {125},
pmid = {41275266},
issn = {1750-1326},
abstract = {BACKGROUND: Alzheimer’s disease (AD) leading to cognitive decline and dementia results from the interplay of multiple interacting dysfunctional biological systems. These systems can be categorized by domain, such as inflammation, cardiovascular health, proteostasis, or metabolism. Specific causes of AD differ between individuals, but each individual is likely to have causes stemming from multiple domains. Personalized multidomain therapy has been proposed as a standard of care for AD.

OBJECTIVES: We sought to enumerate and describe prospective randomized controlled trials (RCTs) for multidomain interventions for AD, and to extract their inclusion criteria, trial design parameters (length, number of participants), and outcome measures. We sought to clarify gaps and opportunities in research and clinical translation.

METHODS: We conducted a scoping review using the standardized PRISMA-ScR methodological framework.

ELIGIBILITY CRITERIA: We include all cohort studies and RCTs for multidomain (also known as multimodal, multicomponent, multidimensional, or multisystem) therapy of any stage of AD, published for all dates through July 28, 2025.

RESULT: There have been 23 studies (completed or reported as ongoing) of multidomain interventions for AD, including 19 RCTs. Of the 15 completed RCTs, 12 demonstrate benefit from their intervention in at least one arm.

CONCLUSIONS: Although these RCTs differ widely in their parameters, the majority support the use of multidomain therapy, and show effect sizes greater than reported for unimodal therapies, including pharmaceuticals. Multidomain therapy should be the standard of care for AD. Multidomain interventions (also known as treatments) should be employed widely, early, and first-line. Treatment or prevention is likely to be most effective at early, presymptomatic stages, but is worthwhile at all stages of disease. In order to influence multiple domains, multiple modes of therapy are likely necessary in all patients. Some individual modes, such as particular lifestyle interventions, may target multiple domains. Nevertheless, most patients will benefit from multiple modes of intervention (multimodal intervention) that together target multiple domains. Standard-of-care guidelines should explicitly include multidomain interventions. Future clinical trials must be designed to iteratively improve multidomain therapies. Payors should embrace reimbursement for effective multidomain intervention, including personalized coaching.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00912-2.},
}

@article {pmid41469705,
year = {2025},
author = {Li, T and Zhang, J and Song, H and Zhang, R and Fan, F and Huang, Z and Zeng, ML and Peng, BW and Zhang, J},
title = {Border-associated macrophages: an emerging perspective from physiological basis and multi-disease roles to the mechanism of vascular cognitive impairment and dementia.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {302},
pmid = {41469705},
issn = {1742-2094},
support = {82501747//the Natural Science Foundation of China/ ; 82571371//the Natural Science Foundation of China/ ; 2025AFC006//the Natural Science Foundation of Hubei Province/ ; PTXM2025032//Medical Sci-Tech Innovation Platform of Zhongnan Hospital, Wuhan University/ ; ZY2023Z018//Key projects of Traditional Chinese Medicine Scientific research in 2023-2024 by Hubei Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Humans ; *Cognitive Dysfunction/pathology/immunology/metabolism ; *Dementia, Vascular/pathology/immunology/metabolism/physiopathology ; Animals ; *Macrophages/pathology/metabolism/immunology ; *Brain/pathology/immunology/metabolism ; },
abstract = {Brain border-associated macrophages (BAMs) are resident immune cells at the border of the central nervous system (CNS), and their physiological functions and roles in neurological diseases have been widely reported. However, the specific mechanisms by which BAMs contribute to vascular cognitive impairment and dementia (VCID) remain unclear. This article systematically reviews the subsets, origin and differentiation, molecular markers of BAMs, and their research progress in various brain diseases such as hypertension, Alzheimer's disease (AD), and stroke. On this basis, this article deeply analyzes the potential hypotheses of BAMs' involvement in the pathogenesis of VCID, including their regulation of neurovascular unit (NVU) homeostasis, their core role in neuroimmune inflammation, their impact on the lipid metabolism pathways in the CNS, and their involvement in the pathogenesis of vascular risk factor-related cognitive impairment (VRFCI). The mechanistic hypotheses proposed in this article aim to provide new perspectives for understanding the pathophysiology of VCID and may open up new directions for the development of early intervention and targeted treatment strategies.},
}

Humans
*Cognitive Dysfunction/pathology/immunology/metabolism
*Dementia, Vascular/pathology/immunology/metabolism/physiopathology
Animals
*Macrophages/pathology/metabolism/immunology
*Brain/pathology/immunology/metabolism

@article {pmid41468784,
year = {2025},
author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D},
title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.},
journal = {Neuropeptides},
volume = {115},
number = {},
pages = {102583},
doi = {10.1016/j.npep.2025.102583},
pmid = {41468784},
issn = {1532-2785},
abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.},
}

@article {pmid41467972,
year = {2025},
author = {Chang, ST and Wu, HY and Chiu, YL and Chuang, YF},
title = {Anti-herpetic treatment reduces dementia risk: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409323},
doi = {10.1177/13872877251409323},
pmid = {41467972},
issn = {1875-8908},
abstract = {BackgroundHuman herpesvirus (HHV) infections, particularly for herpes simplex virus (HSV) and varicella-zoster virus (VZV), may increase dementia risk, yet the protective effects of anti-herpetic medications remained unclear.ObjectiveThis systematic review and meta-analysis of observational studies aimed to examine the association between anti-herpetic medications and dementia, focusing on HSV or VZV-related infections.MethodsThis study followed PRISMA guidelines (CRD42022368318). Cohort or nested case-control studies published from databases' inception to December 2024 were systematically searched in PubMed, MEDLINE, Embase, Cochrane Library, PsycINFO, and Web of Science. Eligible studies evaluated anti-herpetic medications (e.g., acyclovir, famciclovir, ganciclovir, valacyclovir, valganciclovir) and dementia risk in non-demented adults aged ≥50. Pooled adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) were analyzed using random-effects models. Subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity and effect modifiers.ResultsFourteen cohort studies involving more than 10 million older adults were included. To demonstrate the effects of anti-herpetic medications in various clinical scenarios, the meta-analysis compared: diagnosed and treated versus diagnosed but untreated (aHR=0.77, 95% CI: 0.67-0.89); treated versus untreated regardless of diagnosis (aHR=0.90, 95% CI: 0.87-0.94); and diagnosed and treated versus neither diagnosed nor treated (aHR=0.87, 95% CI: 0.78-0.97). Subgroup analysis and meta-regression identified infection severity as a significant modifier (p < 0.0001), explaining 89.01% of heterogeneity.ConclusionsThis systematic review and meta-analysis reveals notable protective effect of anti-herpetic medication usage on dementia, and the effect is especially pronounced in patients with severe alpha herpesvirus infections.},
}

@article {pmid41467438,
year = {2025},
author = {Zhao, J and Wang, J and Guo, X},
title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00924},
pmid = {41467438},
issn = {1673-5374},
abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.},
}

@article {pmid41467376,
year = {2025},
author = {Alexandrova, EG and Abakumova, TR and Ziganshina, LE},
title = {Use of nootropics in Alzheimer's disease: An analysis of regulatory positions and drug policies in the countries of the Commonwealth of Independent States.},
journal = {The International journal of risk & safety in medicine},
volume = {},
number = {},
pages = {9246479251410817},
doi = {10.1177/09246479251410817},
pmid = {41467376},
issn = {1878-6847},
abstract = {ObjectiveTo analyse regulatory positions and drug policies of the Commonwealth of Independent States (CIS), compared to those of the EU, UK, USA i of the nootropics, used in Russia for Alzheimer's disease.MethodsWe searched E-library to reveal the list of nootropics used and studied in Russia for Alzheimer's disease. We assessed official pharmaceutical registries of nine countries for registration status of identified nootropics, 7 National Essential Medicines Lists (EML), and four clinical practice guidelines (CPG) on Alzheimer's disease. We compared the results of Russia with other countries regulatory and policy positions.ResultsE-Library searches identified 11 nootropicspiracetam, citicoline, idebenone, vinpocetine, choline alfoscerate, Cerebrolysin®, Kortexin®, ethylmethylhydroxypyridine succinate, glycine, nicergoline, nimodipine. Eight nootropic have registration for use in all CIS countries (excluding idebenone, nimodipine), four (piracetam, nimodipine, nicergoline, idebenone) - in UK, nimodipine - in the USA, and idebenone - in EU. National EMLs included: nine nootropics (Russia), 8 - Belarus and Kazakhstan, 4 - Uzbekistan, 2 - Armenia. The studied nootropic agents are not included on the WHO Model EML and on the National EML of the Kyrgyz Republic. They are not listed in the CPG for Treatment of dementia and Alzheimer's disease in the USA, the EU, and the UK. Russian CPGs for Alzheimer's disease recommend Cerebrolysin® and choline alfoscerate.ConclusionsThe studied nootropics are registered for use and listed on National EMLs of Russia, Armenia, Belarus, Kazakhstan, Uzbekistan. None is included on the WHO Model EML and the National EML of Kyrgyzstan, Only CPG of the RF recommend using two nootropics as adjuvant therapy of Alzheimer's disease, Cerebrolysin® and choline alfoscerate. CPG of the European Union, the United Kingdom, and the USA do not mention nootropics as potential treatment options for Alzheimer's disease.},
}

@article {pmid41466363,
year = {2026},
author = {de Magalhães, CG and Moldakozhayev, A and Lopez, MV and Bowman, GL and Chhatwal, JP and Kellis, M and Mohs, R and Nisenbaum, L and Quiroz, YT and Raju, RM and Sperling, RA and Moqri, M and Gladyshev, VN},
title = {The Right Person, the Right Treatment, at the Right Time in Alzheimer's Disease: Insights From the 2025 Brain Aging Symposium.},
journal = {Aging cell},
volume = {25},
number = {1},
pages = {e70351},
doi = {10.1111/acel.70351},
pmid = {41466363},
issn = {1474-9726},
mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; *Brain/pathology/metabolism ; *Aging/pathology ; Biomarkers/metabolism ; },
abstract = {On October 22nd, 2025, Brain Aging Symposium took place at Harvard Medical School bringing together leading researchers from academia and partner organizations to discuss recent advances in measuring and monitoring human brain aging trajectories, with a particular focus on Alzheimer's disease (AD). A central theme emerged: achieving "the right treatment for the right person and the right time" through precision medicine approaches. Key advances included the unprecedented validation of plasma-based biomarkers, particularly brain-derived p-Tau217 that can identify seeding AD pathology with remarkable specificity, making large-scale screening newly feasible. Integrating multi-level "omic" modalities, spanning genetic information, molecular biomarkers of nutrition, lipid and protein signatures, neuroimaging measures, cognitive assessments, and lifestyle factors, enhances disease risk modeling and trajectory prediction beyond the capacity of any single marker. Early findings highlight critical roles for nutritional and lipid metabolism, and myelin integrity in brain aging, with cell and sex-specific vulnerabilities identified in response to nutrition, social isolation, and metabolic stress. Computational approaches that combine single-cell genomics, epigenomics, and artificial intelligence have been shown to accelerate causal discovery and therapeutic development. However, significant challenges remain: current biomarkers explain only half the variance in cognitive decline, racial and ethnic differences in biomarker levels lack mechanistic understanding, and scalable tools for comprehensive brain aging assessment are needed. The symposium underscored that preventing AD will require intervening during the preclinical asymptomatic phase. These multimodal screening platforms, coupled with mechanistically driven therapeutics, reduction in modifiable risk factors, including nutrition, vascular health, and social determinants of health, could profoundly impact the field.},
}

Humans
*Alzheimer Disease/therapy/pathology/metabolism
*Brain/pathology/metabolism
*Aging/pathology
Biomarkers/metabolism

@article {pmid41465832,
year = {2025},
author = {Pilśniak, J and Węgrzynek-Gallina, J and Bednarczyk, B and Buczek, A and Pilśniak, A and Chmiela, T and Jarosińska, A and Siuda, J and Holecki, M},
title = {The Role of Glucagon-like Peptide-1 Receptor Agonists in Alzheimer's and Parkinson's Disease: A Literature Review of Clinical Trials.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/life15121893},
pmid = {41465832},
issn = {2075-1729},
abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity due to their metabolic effects. Emerging evidence suggests they may also have neuroprotective effects, indicating their potential as disease-modifying therapies in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Preclinical studies in animal models have demonstrated that GLP-1RAs can reduce neuroinflammation, oxidative stress, neuronal apoptosis, and pathological protein aggregation, while enhancing glucose metabolism and mitochondrial function. This narrative review analyzed results from human clinical trials evaluating GLP-1RAs in AD and PD, based on a search of four databases (Web of Science, Medline, Embase, and Clinical Trials). The analysis included eleven studies. In AD, clinical trials suggest that GLP-1RAs such as liraglutide and semaglutide may enhance brain glucose metabolism, facilitate glucose transport across the blood-brain barrier, and benefit neuronal networks. However, most studies did not demonstrate improvements in cognitive functions or radiological markers. Short-term clinical trials of GLP-1RAs, including exenatide and lixisenatide, demonstrated promising effects on motor and selected non-motor symptoms in patients with PD, but their disease-modifying effects remain unproven. GLP-1RAs showed a favorable safety profile. Despite promising findings, small study populations, heterogeneous protocols, and short observation periods limit definitive conclusions. Further larger, long-term studies are needed, particularly to clarify the risk-benefit balance, weight control, and long-term outcomes.},
}

@article {pmid41465466,
year = {2025},
author = {Xu, C and Owen, JE and Gislason, T and Benediktsdottir, B and Ye, J and Robinson, SR},
title = {Limited Microvascular Remodelling Occurs in the Aged Human Hippocampus in Obstructive Sleep Apnoea.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
doi = {10.3390/ijms262412040},
pmid = {41465466},
issn = {1422-0067},
support = {Not applicable//RMIT University/ ; },
mesh = {Humans ; *Sleep Apnea, Obstructive/pathology/physiopathology/therapy ; Male ; Middle Aged ; Female ; Aged ; *Hippocampus/blood supply/pathology ; *Microvessels/pathology/physiopathology ; Adult ; *Aging/pathology ; *Vascular Remodeling ; Continuous Positive Airway Pressure ; },
abstract = {In mice, intermittent hypoxia is associated with an increase in microvessels in the hippocampus, whereas in humans with obstructive sleep apnoea (OSA), microvessels are lost from the heart and retina. The present study investigated microvascular changes in the hippocampus of patients with OSA, and whether patient age or use of continuous positive airway pressure (CPAP) influence microvascularisation. Using autopsy samples from 31 people with confirmed OSA, microvessels were immunolabelled and quantitatively analysed. Compared to the Low OSA group, the High OSA group had larger mean microvessel diameters in the fimbria and CA4, and greater mean microvessel length in the fimbria, which are indicative of microvascular remodelling. An absence of angiogenesis was indicated by similar mean vessel counts in both OSA severity groups. Increased age was associated with microvascular remodelling in the fimbria only. Treatment with CPAP was not associated with changed patterns of microvascularisation. We conclude that: (i) no evidence was found for angiogenesis in the human hippocampus in OSA or ageing; (ii) increased OSA severity is associated with microvascular remodelling in the fimbria and CA4; (iii) microvascular remodelling does not appear to be influenced by CPAP use; (iv) limited adaptability of the microvasculature may underpin the vulnerability of the hippocampus to hypoxic injury, particularly in severe OSA.},
}

Humans
*Sleep Apnea, Obstructive/pathology/physiopathology/therapy
Male
Middle Aged
Female
Aged
*Hippocampus/blood supply/pathology
*Microvessels/pathology/physiopathology
Adult
*Aging/pathology
*Vascular Remodeling
Continuous Positive Airway Pressure

@article {pmid41465142,
year = {2025},
author = {Machowska, M and Leszek, J and Mikołajczyk-Tarnawa, A and Głowacka, K and Trypka, E and Rąpała, M and Piechota, J and Wiela-Hojeńska, A},
title = {The Diagnostic Reliability of BIN1 and TOMM40 Genotyping in Assessing Dementia Risk.},
journal = {Genes},
volume = {16},
number = {12},
pages = {},
doi = {10.3390/genes16121469},
pmid = {41465142},
issn = {2073-4425},
support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; },
mesh = {Humans ; *Mitochondrial Precursor Protein Import Complex Proteins/genetics ; Male ; Female ; Aged ; *Cognitive Dysfunction/genetics/diagnosis ; *Tumor Suppressor Proteins/genetics ; Polymorphism, Single Nucleotide ; *Adaptor Proteins, Signal Transducing/genetics ; *Alzheimer Disease/genetics/diagnosis ; *Nuclear Proteins/genetics ; Genotype ; *Dementia/genetics/diagnosis ; *Membrane Transport Proteins/genetics ; Genetic Predisposition to Disease ; Case-Control Studies ; Aged, 80 and over ; Middle Aged ; },
abstract = {OBJECTIVES: Alzheimer's disease (AD) and other dementias represent a growing public health concern, highlighting the need for reliable biomarkers for early diagnosis and treatment monitoring. This study evaluated the potential utility of BIN1 and TOMM40 genotyping in diagnosing mild cognitive impairment (MCI) and early-stage dementia.

METHODS: The BIN1 rs744373 and TOMM40 rs2075650 polymorphisms were genotyped in a cohort of 105 individuals diagnosed with MCI or dementia and in 164 cognitively healthy controls. Genotype distributions were compared between the groups, and the potential role of these variants in diagnostic assessment was explored.

RESULTS: A significantly higher frequency of the TOMM40 rs2075650 GG genotype was observed in patients with AD compared with cognitively healthy controls. In contrast, no statistically significant differences in genotype distribution were found among individuals with mild MCI, vascular dementia, or mixed dementia. Furthermore, the distribution of BIN1 rs744373 alleles did not differ significantly across the analyzed groups.

CONCLUSIONS: Data on the effects of BIN1 rs744373 and TOMM40 rs2075650 polymorphisms in MCI and dementia remain limited and inconsistent. In our study, significant differences were observed only for the TOMM40 rs2075650 GG genotype and G allele, which were more frequent in Alzheimer's disease patients than in controls. No significant associations were found for MCI, vascular dementia, or mixed dementia, nor for the BIN1 rs744373 polymorphism. These results suggest that TOMM40 rs2075650 genotyping may serve as an additional marker for assessing AD risk.},
}

Humans
*Mitochondrial Precursor Protein Import Complex Proteins/genetics
Male
Female
Aged
*Cognitive Dysfunction/genetics/diagnosis
*Tumor Suppressor Proteins/genetics
Polymorphism, Single Nucleotide
*Adaptor Proteins, Signal Transducing/genetics
*Alzheimer Disease/genetics/diagnosis
*Nuclear Proteins/genetics
Genotype
*Dementia/genetics/diagnosis
*Membrane Transport Proteins/genetics
Genetic Predisposition to Disease
Case-Control Studies
Aged, 80 and over
Middle Aged

@article {pmid41463129,
year = {2025},
author = {Eroglu, B and Velez, D and Jones, K and Deak, F and Eroglu, A},
title = {Amelioration of Alzheimer's Disease Pathology in Zebrafish by Photobiomodulation.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13123121},
pmid = {41463129},
issn = {2227-9059},
abstract = {Background/Objectives: The zebrafish is a widely used research model due to its characteristics, such as being transparent during development, sharing 70% of its genes with humans, and having conserved features of vertebrate aging, including deterioration of mitochondrial and cognitive functions. While affecting approximately 15% of the world population, neurodegenerative diseases, such as Alzheimer's disease (AD), are currently incurable, requiring testing of alternative treatment strategies. Hence, this study was conducted to test the hypothesis that an optimized photobiomodulation (PBM) therapy improves AD pathology through its multifaceted beneficial effects, including enhancing mitochondrial function and reducing oxidative stress and neuroinflammation. Methods: A pharmacological zebrafish model of AD was developed by adding small amounts (100 nM) of okadaic acid (OKA) directly to fish tanks for nine days. Next, some of OKA-treated and control zebrafish were subjected to an optimized near-infrared PBM therapy while others remain untreated. Results: When examined after OKA treatment, zebrafish brains displayed histological hallmarks of AD including, neurofibrillary tangles, vacuoles, and neuroinflammation. Behavioral tests using a T-maze revealed that OKA-treated zebrafish spent significantly less time in the reward arm than untreated controls (15.2% vs. 50%). In contrast, a sequential PBM therapy significantly reduced formation of neurofibrillary tangles, vacuoles, neuroinflammation, and improved mitochondrial biogenesis in brains of OKA-treated zebrafish while also improving their cognitive function as evidenced by being able to recall the reward arm and spending more time there similar to controls (55 and 57%, respectively). Conclusions: These findings suggest that (1) a fast, cost-effective zebrafish AD model can be developed using OKA treatment and (2) PBM therapy holds promise to ameliorate AD pathology.},
}

@article {pmid41463053,
year = {2025},
author = {N F Guimarães, G and Dos Santos Cardoso, F and Gamboa, L and W Barrett, D and Gonzalez-Lima, F},
title = {Abdominal Photobiomodulation and the Gut-Brain Axis: A Systematic Review of Mechanistic and Translational Evidence.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13123042},
pmid = {41463053},
issn = {2227-9059},
abstract = {Background/Objectives: Bidirectional communication between the gut and brain is central to neurological and psychiatric health, and abdominal photobiomodulation (PBM) has emerged as a promising non-invasive way to modulate this axis by targeting intestinal mitochondria, epithelial integrity, and the microbiota. We systematically reviewed preclinical and clinical evidence on abdominal PBM, alone or in combined protocols, reporting microbiome, metabolic, or neurobehavioral outcomes. Methods: Following PRISMA 2020 recommendations, we searched MEDLINE, Scopus, Web of Science, and ScienceDirect through May 2025 for animal and human studies applying PBM to the abdomen and reporting gut-related, metabolic, or brain-related outcomes. Results: Nine studies met the eligibility criteria (five human, four animal). Human trials, mainly in Parkinson's and Alzheimer's disease, used 630-904 nm light and reported gains in mobility, balance, cognition, and olfaction; one trial also showed microbiota modulation with a decreased Firmicutes:Bacteroidetes ratio. Animal models revealed cognitive improvement, reduced neuroinflammation, dopaminergic neuroprotection, and microbial rebalancing. Mechanistic findings converged on enhanced mitochondrial bioenergetics, redox and anti-inflammatory signaling, vagal activation, and short-chain fatty acid-mediated effects. Conclusions: Current evidence, though limited by small samples, heterogeneous dosimetry, combined treatment sites, and few sham-controlled human trials, suggests that abdominal PBM can influence the gut-brain axis through converging mitochondrial, immune, and microbial mechanisms. Adequately powered randomized trials with standardized dosimetry, validated mechanistic biomarkers, and integrative multi-omics analyses are needed to clarify causal pathways and optimize translational applications.},
}

@article {pmid41462869,
year = {2025},
author = {Sarbu, M and Ica, R and Biricioiu, MR and Dehelean, L and Zamfir, AD},
title = {Glycosphingolipids in Dementia: Insights from Mass Spectrometry and Systems Biology Approaches.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122854},
pmid = {41462869},
issn = {2227-9059},
support = {PN-IV-P2-2.1-TE-2023-0175//UEFISCDI/ ; UAV-IRG-1-2025-8//Aurel Vlaicu University of Arad, Romania/ ; },
abstract = {This narrative literature review synthesizes recent evidence on glycosphingolipid (GSL) dysregulation in dementia, emphasizing discoveries enabled by mass spectrometry (MS) and systems biology. Focusing on the research published within the last decade, we selected studies that are relevant to GSL alterations in dementia and notable for their methodological advances. The findings were conceptually integrated to emphasize key molecular, analytical, and systems-level aspects across the major dementia types. The results from MS-based glycolipidomics in Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease dementia, and Huntington's disease consistently indicate altered GSL metabolism and shared molecular vulnerabilities in neuronal lipid regulation. At the same time, distinct GSL signatures differentiate individual dementias, reflecting the disease-specific mechanisms of neurodegeneration. The literature also reveals that recent advances in high-resolution MS and integrative analytical workflows have shifted GSL research from descriptive to mechanistic, facilitating the detailed mapping of species linked to neuroinflammation, protein aggregation, and synaptic dysfunction. Systems-level analyses combining MS data with other omics approaches increasingly depict GSLs as active regulators of neuronal function rather than inert membrane components. At the same time, emerging trends position GSLs as promising early biomarkers and potential therapeutic targets, while the growing use of artificial intelligence in MS data analysis is accelerating the detection of their subtle patterns, improving cross-disease comparisons. Together, these results reinforce the major role of MS-based platforms in discovering dementia-associated GSLs, identifying therapeutic targets, and influencing future strategies for diagnosis and treatment.},
}

@article {pmid41462867,
year = {2025},
author = {Fonseca, N and Nunes, M and Silva, PMA and Bousbaa, H and Ricardo, S},
title = {Galanthamine Fails to Reverse P-gp-Mediated Paclitaxel Resistance in Ovarian Cancer Cell Lines.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122852},
pmid = {41462867},
issn = {2227-9059},
abstract = {Background: Ovarian cancer has the poorest prognosis of all gynecological malignancies, largely due to its chemoresistance, which poses significant treatment challenges. In this context, drug repurposing emerges as an innovative strategy that employs non-cancer treatments to interact with various signaling pathways, enhancing chemotherapy efficacy while minimizing toxicity. This study investigated the cytotoxic effects of galanthamine, currently used as an Alzheimer's disease, as a potential treatment for high-grade serous carcinoma, both individually and in combination with paclitaxel. Methods: The Presto Blue assay, viability marker assessments, immunocytochemical analysis of apoptosis, and a cumulative assay were employed to evaluate the functionality of P-glycoprotein. Results: The results indicated that galanthamine did not demonstrate cytotoxic or synergistic effects in either high-grade serous carcinoma cell line tested, suggesting that it is not a viable strategy for overcoming paclitaxel resistance in this context. The immunocytochemistry analysis indicated that galanthamine does not affect the expression of proteins related to cell viability and proliferation and is not associated with chemoresistance. Additionally, functional assays showed that galanthamine treatment did not affect its drug efflux function at the cellular level. Conclusions: Overall, the results indicate that galanthamine is unsuitable for reversing paclitaxel resistance despite some literature suggesting its potential interaction with P-glycoprotein.},
}

@article {pmid41461739,
year = {2025},
author = {Palachai, N and Buranrat, B and Pariwatthanakun, C and Noisa, P and Mairuae, N},
title = {Neuroprotective effects of Cratoxylum formosum (L.) leaf extract on β-amyloid-induced injury in human neuroblastoma SH-SY5Y cells.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44730},
pmid = {41461739},
issn = {2045-2322},
support = {//the Faculty of Medicine, Mahasarakham University/ ; //Thai Traditional Medical Knowledge Fund/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/toxicity ; *Plant Extracts/pharmacology/chemistry ; *Plant Leaves/chemistry ; *Neuroprotective Agents/pharmacology/chemistry ; Cell Line, Tumor ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Cell Survival/drug effects ; *Neuroblastoma/metabolism/pathology/drug therapy ; Cyclic AMP Response Element-Binding Protein/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; *Peptide Fragments/toxicity ; Caspase 3/metabolism ; Apoptosis/drug effects ; Phosphorylation/drug effects ; },
abstract = {In Alzheimer's disease (AD), Amyloid beta peptide (Aβ), the primary constituent of senile plaques, has been documented as triggering oxidative stress and leading to the death of neuronal cells. Therefore, this research aims to investigate how the Cratoxylum formosum (L.) leaf extract mitigates oxidative stress and cellular damage induced by Aβ in SH-SY5Y cells. The SH-SY5Y cells were treated with Cratoxylum formosum (L.) extract both with and without Aβ25-35. Neuroprotection was evaluated through viability and lactate dehydrogenase (LDH) assays, accompanied by an analysis of various mechanisms including caspase-3/7 activity, levels of reactive oxygen species (ROS), phosphorylation of protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (ERK1/2), and cAMP-responsive element binding protein (CREB), expression of B-cell lymphoma 2 (Bcl-2) proteins, as well as catalase (CAT) and superoxide dismutase (SOD) activities. Results indicated an escalation in oxidative stress in cells exposed to Aβ, evidenced by increased ROS levels. Aβ further exacerbated caspase-3/7 activity, LDH release, and a decline in cell viability. Conversely, treatment with Cratoxylum formosum (L.) extract exhibited a concentration-dependent reduction in Aβ-induced neurotoxicity, manifesting in enhanced cell survival, reduced LDH release and ROS production, and suppression of caspase-3/7 activity. Moreover, it led to increased phosphorylation of Akt, ERK1/2, CREB, upregulated expression of Bcl-2 proteins, and enhanced activity of SOD and CAT. High-performance liquid chromatography (HPLC) analysis identified chlorogenic acid, 1,5-dicaffeoylquinic acid, and ferulic acid as the major phenolic constituents of Cratoxylum formosum (L.) extract. These results imply that the extract may provide protective effects against Aβ-induced neurotoxicity, although further studies are required to clarify its role in AD.},
}

Humans
*Amyloid beta-Peptides/toxicity
*Plant Extracts/pharmacology/chemistry
*Plant Leaves/chemistry
*Neuroprotective Agents/pharmacology/chemistry
Cell Line, Tumor
Oxidative Stress/drug effects
Reactive Oxygen Species/metabolism
Cell Survival/drug effects
*Neuroblastoma/metabolism/pathology/drug therapy
Cyclic AMP Response Element-Binding Protein/metabolism
Proto-Oncogene Proteins c-akt/metabolism
*Peptide Fragments/toxicity
Caspase 3/metabolism
Apoptosis/drug effects
Phosphorylation/drug effects

@article {pmid41461684,
year = {2025},
author = {Saremi, M and Safari, S and Alikhani, MY and Komaki, A and Siadat, SD and Asghari, B},
title = {Evidence for neuroprotection by Bacillus coagulans ATCC 7050 via synaptic plasticity and oxidative balance in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {44690},
pmid = {41461684},
issn = {2045-2322},
support = {Grant Number: 140303292888//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Oxidative Stress/drug effects ; Male ; *Neuronal Plasticity/drug effects ; Rats ; Rats, Wistar ; *Bacillus coagulans/physiology ; Disease Models, Animal ; Hippocampus/metabolism ; Amyloid beta-Peptides ; *Probiotics/pharmacology/administration & dosage ; Long-Term Potentiation ; *Neuroprotection ; Superoxide Dismutase/metabolism ; Memory, Short-Term ; Glutathione Peroxidase/metabolism ; Malondialdehyde/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic impairment, and oxidative stress. Probiotics with antioxidant and anti-inflammatory properties have been proposed as potential adjunctive strategies. This study examined whether oral administration of Bacillus coagulans ATCC 7050 could attenuate hippocampal oxidative stress, modulate synaptic plasticity, and influence spatial working memory in an Aβ1-42-induced rat model of AD. Adult male Wistar rats were assigned to Sham, AD, BC (probiotic only), and AD + BC groups. Working memory was assessed by Y-maze, synaptic function by perforant path-dentate gyrus long-term potentiation (LTP) recordings, and oxidative status by hippocampal malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) assays. AD rats exhibited reduced alternation percentage, impaired LTP (fEPSP slope and PS amplitude), elevated MDA, and decreased SOD and GPx activities versus Sham. B. coagulans treatment improved alternation percentage without affecting total entries, preserved PS amplitude from 30 min post-HFS, reduced MDA, and restored SOD activity, with partial GPx recovery. fEPSP slope remained reduced. These findings suggest B. coagulans ATCC 7050 mitigates oxidative stress, preserves neuronal excitability, and improves working memory in an Aβ-based AD model, supporting further investigation of its potential as a safe adjunct in early-stage disease.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Oxidative Stress/drug effects
Male
*Neuronal Plasticity/drug effects
Rats
Rats, Wistar
*Bacillus coagulans/physiology
Disease Models, Animal
Hippocampus/metabolism
Amyloid beta-Peptides
*Probiotics/pharmacology/administration & dosage
Long-Term Potentiation
*Neuroprotection
Superoxide Dismutase/metabolism
Memory, Short-Term
Glutathione Peroxidase/metabolism
Malondialdehyde/metabolism

@article {pmid41461311,
year = {2025},
author = {Li, R and Wu, X and Yao, J and Chen, J and Shui, X and Zheng, X and Tian, W and Wang, L and Zhou, Y and Zhang, T and Chen, D and Liu, Y and Lee, TH},
title = {Selective degradation of DAPK1 via a novel hydrophobic tagging attenuates tau pathology in Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.12.037},
pmid = {41461311},
issn = {2090-1224},
abstract = {INTRODUCTION: The upregulation of death-associated protein kinase 1 (DAPK1) is involved in tau hyperphosphorylation, neuronal apoptosis and cognitive dysfunction, which are key pathological features of Alzheimer's disease (AD). This result suggests that DAPK1 is novel therapeutic target for AD.

OBJECTIVES: This study aimed to evaluate the efficacy and mechanism of action of CJ1, a novel hydrophobic tagging (HyT)-based degrader, in targeting DAPK1 and alleviating in AD.

METHODS: A library of HyT-based bifunctional molecules was synthesized and systematically screened for their ability to degrade DAPK1 in vitro. CJ1 emerged as the most potent candidate degrader of DAPK1, and its capacity to induce DAPK1 degradation via the proteasome system was further evaluated. Its effects on tau phosphorylation and neuronal viability were evaluated in multiple cellular models. The in vivo efficacy of systemic CJ1 administration was assessed in two tau-related pathology (tauopathy) mouse models, AAV-hTau-P301L and hTau transgenic mice. Behavioral, biochemical, and histological analyses were performed to evaluate cognitive function, tau pathology, neuroinflammation, neurodegeneration, and safety.

RESULTS: CJ1 selectively promoted the posttranslational degradation of DAPK1 by the proteasome system without affecting DAPK1 mRNA expression. In vitro studies demonstrated that CJ1 significantly reduced tau phosphorylation at multiple AD-related sites. In vivo, CJ1 effectively penetrated the BBB, decreased the levels of both the soluble and insoluble forms of hyperphosphorylated tau, and suppressed the formation of neurofibrillary tangles. Additionally, CJ1 treatment restored synaptic and dendritic structures, enhanced spatial learning and memory, attenuated neuroinflammatory responses, preserved neuronal populations, and produced no evidence of systemic toxicity.

CONCLUSION: CJ1 functions as a potent and selective degrader of DAPK1, exerting neuroprotective effects by reducing tau hyperphosphorylation and preserving neuronal structural integrity. These findings support DAPK1 as a promising therapeutic target and suggest that further preclinical studies are warranted to evaluate CJ1 as a potential treatment for tauopathies associated with AD.},
}

@article {pmid41460672,
year = {2025},
author = {Sun, L and Wei, G and Ji, F and Ding, Y and Fan, J and Xu, Y and He, C and Zhou, Y and Liu, Z and Sun, Z and Zhou, D},
title = {Proteome-wide association study identifies novel Alzheimer's disease-associated proteins.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251409352},
doi = {10.1177/13872877251409352},
pmid = {41460672},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease with limited prevention and treatment options.ObjectiveWe aimed to identify proteins with genetically regulated plasma levels associated with AD and its related phenotypes.MethodsWe conducted a proteome-wide association study (PWAS) using Olink-based plasma proteomes (N = 45,540) from the UK Biobank Pharma Proteomics Project (UKB-PPP) and a large-scale genome-wide association study for AD (N case = 85,934, N control = 401,577). To validate and expand these findings, we conducted longitudinal analyses of AD and mild cognitive disorder (MCD) over a 13.7-year follow-up, along with genetic-based PWAS analyses and cross-sectional studies on hippocampal volume. Protein-protein interaction networks were constructed to explore mechanistic association.ResultsWe identified 30 AD-associated plasma proteins by PWAS, including 17 previously reported and 13 novel candidates (including FES, LRP11, and HDGF). Longitudinal cohort studies supported the role of PILRB and FES in AD and/or MCD. Additionally, the genetically determined higher levels of LRP11 were found to be associated with an increased hippocampal volume, including its subdivisions, along with a reduced risk of AD. In contrast, higher plasma levels of HDGF were linked to a decreased hippocampal volume, accompanied by an increased risk of AD. Protein-protein interaction analysis linked PILRA, PILRB, FES, and LRP11 to several pathological proteins associated with AD, including BIN1, ABCA7, and SORL1.ConclusionsThis study identified 13 novel candidates, with potential roles in hippocampal volume and AD risk, providing insights into disease mechanisms.},
}

@article {pmid41460605,
year = {2025},
author = {Fassbender, RV and Kehm, C and Otta, AL and Fink, GR and Onur, OA},
title = {Repetitive transcranial magnetic stimulation enhances alpha power in Alzheimer's disease patients.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251406972},
doi = {10.1177/13872877251406972},
pmid = {41460605},
issn = {1875-8908},
abstract = {BackgroundWith Alzheimer's disease (AD) presenting an ongoing challenge, innovative treatment methods are essential. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising noninvasive intervention, particularly targeting alpha band oscillations associated with AD-related cognitive decline.ObjectiveThis study aimed to investigate the effects of low-intensity rTMS over posterior cortical areas on alpha band oscillations and memory performance in AD patients compared to age-matched healthy controls.MethodsIn a single-blinded, sham-controlled rTMS-EEG study, we examined 14 amyloid-positive AD patients and 14 age-matched healthy controls. Continuous EEG was recorded at rest (eyes closed) before, during, and after stimulation. During stimulation, participants completed an episodic memory task.ResultsWe were able to demonstrate that during rTMS alpha power increased compared to sham, with a notable 25% increase observed in AD patients. However, comparison of memory performance under the sham and stimulation conditions revealed no significant stimulation effect.ConclusionsThese findings support and extend current knowledge of noninvasive brain stimulation mechanisms. Our results suggest that alpha frequency-tuned rTMS over posterior cortical areas can modulate pathological brain activity in AD patients even at low intensities. Given the limited sample size and moderate effect sizes, results should be interpreted with caution. Nevertheless, our results warrant further studies with long-term EEG-rTMS protocols to evaluate the potential therapeutic benefit.},
}

@article {pmid41460506,
year = {2025},
author = {Bernard, PJ and Więckowska, A and Grosjean, S and Godyń, J and Sałat, K and Detka, J and Palacz, N and Tyrybon, W and Jończyk, J and Szałaj, N and Zaręba, P and Martin, H and Maj, M and Jozwiak, K and Marco-Contelles, J and Ismaili, L},
title = {First Sustainable One-Pot Tandem Hantzsch Multicomponent Reaction/Click Reaction Approach for Novel Multitarget-Directed Ligands in Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00806},
pmid = {41460506},
issn = {1948-7193},
abstract = {This study explores novel multitarget-directed ligands (MTDLs) showing anticholinesterase, antioxidant, neuroprotective, and calcium channel inhibitory activities, as promising compounds for Alzheimer's disease (AD) treatment. The rational design combined dihydropyridines (DHPs), known for calcium channel blocking and neuroprotective properties, with tacrine, a cholinesterase inhibitor. The key innovation of this work lies in the one-pot tandem Hantzsch multicomponent/click reaction used to synthesize new 18 DHPs IIIa-r. This sustainable and original approach aligns with green chemistry principles by reducing waste, energy consumption, and derivatives formation. Notably, DHP IIIj and IIIk demonstrated a multitarget profile and effectively reversed scopolamine-induced amnesia in a mouse model, showcasing its antiamnesic properties. These results suggested that DHP IIIj and IIIk hold promise as innovative therapeutic candidates for AD, validating the potential of MTDL strategy and highlighting the one-pot tandem synthesis as a significant advancement in medicinal chemistry.},
}

@article {pmid41460033,
year = {2026},
author = {Hu, XH and Jin, Q and Xie, JL and Wu, CL and Pan, JP},
title = {Docosahexaenoic acid modulates microglial autophagy via miR-589-5p/toll-like receptor 4 axis in Alzheimer's disease.},
journal = {Neuroreport},
volume = {37},
number = {2},
pages = {77-85},
doi = {10.1097/WNR.0000000000002236},
pmid = {41460033},
issn = {1473-558X},
mesh = {*Alzheimer Disease/metabolism ; *Autophagy/drug effects ; *MicroRNAs/metabolism ; *Docosahexaenoic Acids/pharmacology ; *Toll-Like Receptor 4/metabolism/drug effects ; Humans ; *Microglia/drug effects/metabolism ; Animals ; Male ; Mice ; Female ; Aged ; Amyloid beta-Peptides ; Cell Line ; },
abstract = {OBJECTIVE: To investigate the neuroprotective mechanism by which docosahexaenoic acid (DHA) promotes microglial autophagy via the miR-589-5p/toll-like receptor 4 (TLR4) axis in Alzheimer's disease.

METHODS: In vitro, BV2 microglial cells were treated with Aβ25-35 to establish an Alzheimer's disease model and subjected to DHA treatment with or without miR-589-5p inhibition and TLR4 overexpression. Cytotoxic effects were assessed by methylthiazolyldiphenyl-tetrazolium bromide assays. Autophagy markers (LC3-II/I ratio, Beclin1, and p62) were evaluated by Western blot and immunofluorescence. The miR-589-5p/TLR4 interaction was assessed using dual luciferase assays. For clinical validation, peripheral blood samples from healthy controls, patients with mild Alzheimer's disease, and patients with severe Alzheimer's disease (n = 30 each) were analyzed for miR-589-5p and TLR4 mRNA expression via quantitative reverse transcription PCR (qRT-PCR).

RESULTS: In cellular assays, DHA significantly enhanced autophagy by increasing the LC3-II/I ratio and Beclin1 expression while decreasing p62 levels (P < 0.05). Mechanistic validation showed that miR-589-5p inhibition abolished DHA's autophagy-promoting effects, while TLR4 overexpression reversed these benefits. Conversely, miR-589-5p mimic treatment rescued autophagy even under TLR4 overexpression conditions. Dual-luciferase assays confirmed that miR-589-5p directly targets TLR4. Clinically, qRT-PCR analysis revealed that miR-589-5p expression was downregulated and TLR4 expression was upregulated in Alzheimer's disease patients compared to healthy controls, and these alterations were correlated with disease severity (P < 0.05).

CONCLUSION: DHA enhances microglial autophagy via a novel miR-589-5p/TLR4 regulatory axis, a potential Alzheimer's disease therapy and biomarker for Alzheimer's disease progression.},
}

*Alzheimer Disease/metabolism
*Autophagy/drug effects
*MicroRNAs/metabolism
*Docosahexaenoic Acids/pharmacology
*Toll-Like Receptor 4/metabolism/drug effects
Humans
*Microglia/drug effects/metabolism
Animals
Male
Mice
Female
Aged
Amyloid beta-Peptides
Cell Line

@article {pmid41460031,
year = {2026},
author = {Fu, C and Kan, Y and Guo, K and Jiang, L and Zhang, Y and Dong, H and Xie, J},
title = {Tenuigenin ameliorates Alzheimer's disease by targeting MAP2K1: integrated evidence from network pharmacology and experimental validation.},
journal = {Neuroreport},
volume = {37},
number = {2},
pages = {53-66},
doi = {10.1097/WNR.0000000000002239},
pmid = {41460031},
issn = {1473-558X},
support = {gzwkj2025-129//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; gzwkj2025-130//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; 20222121020675//Project of the Heilongjiang Provincial Health and Family Planning Commission/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Network Pharmacology/methods ; *Neuroprotective Agents/pharmacology ; *Drugs, Chinese Herbal/pharmacology ; Molecular Docking Simulation ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; },
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily characterized by progressive cognitive impairment and synaptic dysfunction. Despite substantial research efforts, effective therapeutic options remain limited. Tenuigenin (TEN), a principal bioactive constituent isolated from the traditional Chinese medicinal herb Polygala tenuifolia, has demonstrated promising neuroprotective effects.

METHODS: This study adopted a comprehensive multitiered approach, combining network pharmacology, machine learning, molecular modeling, and in-vitro experiments, to elucidate the therapeutic targets and mechanisms of TEN in AD. Computational analyses identified mitogen-activated protein kinase kinase 1 (MAP2K1) as a critical target, mediating the effects of TEN. Gene set enrichment analysis indicated that TEN could activate the 26S proteasome pathway, promoting the degradation of neurotoxic proteins, such as amyloid-β (Aβ), thereby reducing their pathological accumulation.

RESULTS: Immune infiltration analysis further revealed that TEN could modulate the distribution of activated natural killer cells and M0 macrophages, playing a role in restoring immune balance in the AD microenvironment. Molecular docking and dynamics simulations demonstrated strong binding affinity and structural compatibility between TEN and MAP2K1. Experimental validation using Aβ-treated SH-SY5Y cells indicated that TEN significantly enhanced cell viability and suppressed MAP2K1 protein expression.

CONCLUSION: In conclusion, this study provided the first integrated evidence that TEN exerts neuroprotective effects in AD by targeting MAP2K1. These findings highlight the multitarget, multipathway therapeutic potential of TEN and support its development as a natural agent for AD prevention and treatment.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
Network Pharmacology/methods
*Neuroprotective Agents/pharmacology
*Drugs, Chinese Herbal/pharmacology
Molecular Docking Simulation
Amyloid beta-Peptides/metabolism
Cell Line, Tumor

@article {pmid41458258,
year = {2026},
author = {Jing, C and Li, J and Yu, D and Chao, M and Yan, H and Ge, K and Ma, G and Wang, J and Gao, F and Zhang, G},
title = {Heterotrimetallic Au@Cu2Se nanozymes target inflamed neurons via suppression of oxidative stress and apoptosis to alleviate Alzheimer's disease.},
journal = {Materials today. Bio},
volume = {36},
number = {},
pages = {102646},
pmid = {41458258},
issn = {2590-0064},
abstract = {Neuronal dysfunction mediated by oxidative stress and amyloid-β (Aβ) deposition is widely recognized as a core mechanism in the pathogenesis of Alzheimer's disease (AD). Aβ oligomers specifically interact with key mitochondrial proteins-such as alcohol dehydrogenase, cyclophilin D, and ATP synthase-markedly increasing reactive oxygen species (ROS) production, which leads to mitochondrial membrane potential collapse and disruption of energy metabolism. Although cuprous selenide and gold nanospheres can mimic the catalytic activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD), effectively scavenge excess ROS, restore mitochondrial membrane potential, and promote ATP synthesis through synergistic action, their therapeutic potential is limited by poor targeting specificity in vivo. Moreover, while antioxidant nanoagents show promise in mitigating oxidative stress, their non-specific distribution often necessitates high doses, raising potential off-target toxicity concerns and reducing treatment efficacy. Therefore, developing a delivery system that combines multifunctional neuroprotection with precise targeting to diseased microenvironments remains an urgent need. To address this, we functionalized the surface of Au@Cs nanoparticles with hyaluronic acid (HA) to construct a CD44-targeted Au@Cs-HA-PEG nanosystem. By taking advantage of the high expression of CD44 in microglia and astrocytes under inflammatory conditions, the precise targeting of inflammatory regions in the brains of AD model mice was promoted. In vitro experiments demonstrated that Au@Cs-HA-PEG effectively reduced ROS levels in HT22 cells, reversed mitochondrial membrane potential attenuation, and restored neuronal function. In vivo results showed that these nanoparticles achieved rapid brain enrichment, significantly reduced Aβ plaque deposition and neuroinflammation, and markedly improved learning, memory, and cognitive abilities in AD mice. In conclusion, this study confirms that the Au@Cs-HA-PEG nanosystem ameliorates cognitive dysfunction in AD mice by regulating ROS homeostasis, offering a novel strategy and experimental foundation for targeted therapy of Alzheimer's disease.},
}

@article {pmid41457950,
year = {2025},
author = {Algeciras-Schimnich, A and Theobald, JP and Figdore, DJ and Ashrafzadeh Kian, S and Bornhorst, JA},
title = {False positive plasma p-tau217 results associated with heterophilic antibody interference: A potential clinical pitfall.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71045},
pmid = {41457950},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/blood/immunology ; *Alzheimer Disease/blood/diagnosis ; *Antibodies, Heterophile/blood ; False Positive Reactions ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Immunoassay ; Phosphorylation ; Female ; Male ; Aged ; Peptide Fragments ; },
abstract = {INTRODUCTION: Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as one of the most promising blood-based biomarkers for Alzheimer's disease (AD). While rare, heterophilic antibodies (HAb) are a persistent potential confounding factor in immunoassays.

METHODS: Potential HAb interference in the Lumipulse G pTau217 assay in samples exhibiting concentrations > 10 pg/mL were investigated. Samples were subjected to HAb blocking reagent (HBT), and in some cases, polyethylene glycol (PEG) precipitation and serial dilutions.

RESULTS: In 14 of the 15 suspected HAb cases, HBT treatment greatly reduced measured p-tau217 concentrations. and in one of three specimens selected for further investigation, reduced Aβ42 concentrations PEG precipitation in the three selected samples also reduced p-tau217 concentrations, while serial dilution yielded mixed effects. Control specimens were unaffected by sample treatment or dilutions.

DISCUSSION: HAb may result in falsely elevated p-tau217 and p-tau217/Aβ42 ratio. HAb interference should be considered in cases of unusually high p-tau217 concentrations prior to clinical interpretation.

HIGHLIGHTS: Potential heterophile antibody (HAb) interference in the Lumipulse p-tau217 immunoassay was investigated. Investigation was performed using HAb blocking reagent, and in some cases also using PEG precipitation . Patients with p-tau217 concentrations > 10 pg/mL exhibited positive HAb interference in 14 of 15 cases. HAb interference can lead to falsely positive p-tau217/Aβ42 ratios.},
}

Humans
*tau Proteins/blood/immunology
*Alzheimer Disease/blood/diagnosis
*Antibodies, Heterophile/blood
False Positive Reactions
Amyloid beta-Peptides/blood
Biomarkers/blood
Immunoassay
Phosphorylation
Female
Male
Aged
Peptide Fragments

@article {pmid41457949,
year = {2025},
author = {Chen, Q and Wen, Q and Zhong, T and Liu, J and Gao, H},
title = {Deep cervical lymphaticovenous anastomosis for Alzheimer's disease: A narrative review.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71038},
pmid = {41457949},
issn = {1552-5279},
support = {No.B2025292//Medical Scientific Research Foundation of Guangdong Province/ ; GMUCR2025-02028//Plan on enhancing scientific research in GMU，Guangdong, China/ ; },
mesh = {Humans ; *Alzheimer Disease/surgery ; *Lymphatic Vessels/surgery ; *Anastomosis, Surgical/methods ; *Glymphatic System/surgery ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder with limited treatment options. Recent discoveries of the glymphatic system and meningeal lymphatic vessels (MLVs) have highlighted their critical role in clearing metabolic waste-including amyloid beta and tau proteins-from the brain. Dysfunction of these systems contributes to AD pathogenesis by impairing the clearance of neurotoxic proteins. Deep cervical lymphaticovenous anastomosis (dcLVA) is an innovative microsurgical technique designed to enhance cerebral waste drainage by anastomosing deep cervical lymphatic channels to adjacent veins. This narrative review synthesizes current evidence on the mechanisms, applications, and emerging perspectives of dcLVA for AD. Early studies suggest potential short-term improvements in cognitive scores and neuroimaging biomarkers after surgery, with an acceptable safety profile. However, the evidence is limited to small prospective cohorts and case reports, underscoring the need for larger, randomized controlled trials to validate its efficacy and long-term benefits. dcLVA represents a promising surgical intervention for select patients, particularly those with moderate-to-severe AD who have failed conventional pharmacotherapy, but it requires careful patient selection and further investigation. HIGHLIGHTS: This review proposes deep cervical lymphaticovenous anastomosis (dcLVA) as a mechanism driven surgery that may enhance clearance of amyloid beta (Aβ) and tau through the brain, meningeal, and deep cervical drainage pathways. Early human evidence from a single arm cohort and case reports suggests short term cognitive and imaging signals with acceptable perioperative safety. dcLVA is not recommended as a first line option for early Alzheimer's disease (AD) and may be considered for moderate to severe AD or for patients who are refractory to pharmacotherapy and have objective evidence of drainage impairment. Standardized patient selection and longitudinal imaging and biomarker monitoring are recommended, including Aβ and tau positron emission tomography (PET), diffusion tensor imaging (DTI) analysis along the perivascular space, and cerebrospinal fluid (CSF) or plasma panels. Systemic safety remains an important uncertainty, and future trials should include longitudinal surveillance of hepatic, renal, and hematologic function. Multicenter randomized controlled trials (RCTs) are urgently needed with 12 month Clinical Dementia Rating Sum of Boxes (CDR SB) as a primary endpoint, transparent reporting, and evaluation of combination strategies with anti Aβ therapies.},
}

Humans
*Alzheimer Disease/surgery
*Lymphatic Vessels/surgery
*Anastomosis, Surgical/methods
*Glymphatic System/surgery
Amyloid beta-Peptides/metabolism

@article {pmid41457120,
year = {2025},
author = {Jiang, T and Ma, W and Dong, W and Zhou, H and Mao, X},
title = {Ferroptosis-associated transcriptional factors in neurological diseases: molecular mechanisms and therapeutic prospects.},
journal = {Experimental & molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41457120},
issn = {2092-6413},
abstract = {Ferroptosis, a newly discovered type of regulatory cell death with iron-dependent accumulation of lipid peroxides, is widely discussed in a plethora of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and spinal cord injury. There are many preclinical and clinical evidences supporting the critical role of ferroptosis in these neurologic conditions, despite the molecular machinery by which ferroptosis modulates brain dysfunction remains uncharacterized. Transcription factors (TFs) are core components of the machinery that manipulates ferroptosis process genetically. Until now, there is no report on the summarization of role of ferroptosis-associated TFs in neurological diseases. Therefore, here we provided the basic knowledge regarding the regulation of TFs on ferroptotic processes including iron metabolism, antioxidant defense and lipid peroxidation. In addition, we also discussed the recent advances in our understanding of ferroptosis-related TFs in the emerging hallmarks of neurological diseases. The fact that Nrf2 activator RTA-408 is approved for clinical evaluation (phase 2 clinical trial) of its efficacy and safety in patients with Alzheimer's disease supports this notion. Future research on proteolysis-targeting chimera (PROTAC) and gene therapy holds promise for optimization of neurological disease treatment.},
}

@article {pmid41456743,
year = {2025},
author = {Sabrina, T and Federica, F and Zaira, B and Lucia, G and Manuela, M and Loredana, LP and Gloria, V and Antonella, F},
title = {INVESTIGATION OF DIPYRIDAMOLE-ELICITED SIGNALING IN THE BRAIN OF NIEMANN PICK TYPE C MICE: A MULTI-OMIC STUDY.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111708},
doi = {10.1016/j.brainresbull.2025.111708},
pmid = {41456743},
issn = {1873-2747},
abstract = {Niemann Pick type C1 (NPC1) is a rare, fatal disorder characterized by endo-lysosomal (EL) lipid accumulation that leads to damage of both peripheral organs and central nervous system, with cerebellum and hippocampus being particularly affected. Currently very few therapeutic options exist in Europe for NPC. In fact, miglustat is the only approved drug and L-acetylleucine was recently granted for marketing authorization by European Medicine Agency. Thus, the identification of new treatments is mandatory. We have previously demonstrated that dipyridamole (DIP), an approved medicine that is clinically employed as an antiplatelet agent, could rescue recognition memory and increase hippocampal expression of calbindin. On the contrary, the drug was unable to improve cerebellar-dependent motor function. In order to elucidate the mechanism of these region-specific changes induced by DIP, in this work we performed a multi-omic analysis of genes and proteins modulated by the treatment in the hippocampus and cerebellum of a mouse model of NPC1 (Npc1[-/-]). Our results revealed that DIP significantly affected various pathways in the hippocampus at protein level, but it had no significant impact on pathways in the cerebellum (either at gene or protein level). Interestingly, the most affected pathways in the hippocampus of Npc1[-/-] mice administered with DIP were those related to cGMP-PKG activation and to mitochondrial function. Our results paved the way to test DIP in experimental models of other neurodegenerative disorders, such as Alzheimer's disease that is similarly marked by hippocampal and mitochondrial dysfunctions.},
}

@article {pmid41456527,
year = {2025},
author = {Li, X and Ji, W and Wu, X and Cai, J and Zheng, M and Zhang, X and Liu, P and Wang, G and Li, X and Wang, S and Huo, Z and Wang, Q and Song, Z and Li, D and Zhou, S and Sun, H and Ma, X and Zou, L and Gao, W},
title = {Cerebralcare Granule® restores intracranial lymphatic drainage system to support proactive brain health in Alzheimer's disease models.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {150},
number = {},
pages = {157617},
doi = {10.1016/j.phymed.2025.157617},
pmid = {41456527},
issn = {1618-095X},
abstract = {BACKGROUND: Impairment of the intracranial lymphatic drainage system significantly contributes to Alzheimer's disease (AD) by facilitating the accumulation of neurotoxic amyloid-β (Aβ) and tau proteins. Restoring lymphatic function offers a promising preventive strategy against early-stage AD pathology.

PURPOSE: This study aimed to evaluate the effects and mechanisms of Cerebralcare Granule® (CG), a traditional Chinese medicine formula, on cognitive impairment and pathological markers in AD mouse models by modulating intracranial lymphatic clearance pathways.

METHODS: Six-month-old APP/PS1 transgenic mice and wild-type controls received oral administration of CG or donepezil for two months. Behavioral assessments included the Morris water maze, open field, Y-maze, novel object recognition, and passive avoidance tests. Immunohistochemistry, immunofluorescence, and Western blot analyses were used to assess Aβ deposition, glymphatic clearance, astrocytic aquaporin-4 (AQP4) polarization, meningeal lymphangiogenesis, and blood-brain barrier integrity. Tracer-based in vivo imaging confirmed improved CSF influx and efflux dynamics. Brain-penetrant compounds of CG were identified using UPLC-MS/MS, MALDI-TOF-MS imaging, and network pharmacology.

RESULTS: CG treatment significantly improved cognitive performance, reduced Aβ burden, enhanced glymphatic transport, and promoted meningeal lymphatic drainage in APP/PS1 mice. CG restored perivascular AQP4 polarization, improved cerebrospinal fluid-interstitial fluid exchange, facilitated waste removal to cervical lymph nodes, and protected the integrity of the blood-brain barrier. Major brain-penetrant compounds-paeoniflorin, rhynchophylline, and ethyl gallate-were found to target lymphatic signaling pathways (AQP4, VEGFC, VEGFR3, PROX1) effectively.

CONCLUSION: CG exerts protective effects against cognitive impairment and AD pathology by reinforcing the structural and functional integrity of the intracranial lymphatic drainage system, highlighting a novel therapeutic avenue for proactive brain health management in early-stage AD.},
}

@article {pmid41456355,
year = {2025},
author = {Haixia, T and Bo, X},
title = {Exercise impact on IRE1α signaling: Novel insights into Alzheimer's disease prevention and treatment.},
journal = {Biochemical and biophysical research communications},
volume = {797},
number = {},
pages = {153156},
doi = {10.1016/j.bbrc.2025.153156},
pmid = {41456355},
issn = {1090-2104},
abstract = {Endoplasmic reticulum stress (ERS) and its downstream signaling play a central role in neuroinflammation in Alzheimer's disease (AD). Among them, IRE1α, as a key sensor of ER stress, is a pivotal molecule connecting stress to inflammation. Its aberrant activation drives neuroinflammation, which in turn exacerbates Aβ deposition, Tau pathology, and cognitive decline. Therefore, targeting the IRE1α signaling pathway has become a potential strategy for AD intervention. Recent studies suggest that exercise can alleviate ER stress and directly or indirectly inhibit the excessive activation of IRE1α, thereby reducing its downstream inflammatory signals. This review aims to systematically elucidate the pathogenic mechanism of the IRE1α inflammatory signaling pathway in AD. It also focuses on exploring the evidence of the neuroprotective effect of exercise through regulating this pathway, providing new theoretical basis and direction for exercise-based prevention and treatment of AD.},
}

@article {pmid41455872,
year = {2025},
author = {Marei, HE},
title = {Epigenetic Editing in Neurological and Neuropsychiatric Disorders: Pioneering Next-Gen Therapeutics for Precision Gene Control.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {330},
pmid = {41455872},
issn = {1559-1182},
mesh = {Humans ; *Epigenesis, Genetic/genetics ; *Gene Editing/methods ; *Nervous System Diseases/genetics/therapy ; Animals ; *Mental Disorders/genetics/therapy ; *Genetic Therapy/methods ; *Precision Medicine/methods ; Epigenome Editing ; },
abstract = {Epigenetic editing has emerged as a promising approach in the treatment of neurological and neuropsychiatric disorders, enabling the precise and enduring modification of genes associated with these conditions. Interventions that focus on chromatin, such as programmable systems like CRISPR/dCas9, zinc-finger proteins, and TALEs linked to epigenetic effector domains, enable the modification of DNA methylation, histone modifications, and noncoding RNA control at specific loci. This work integrates current progress in understanding the epigenetic landscape of neurological neuropsychiatric disorders, highlighting the functions of DNA methylation (de novo vs maintenance, active versus passive demethylation), histone remodeling, and context-dependent gene regulation. We emphasize that the dysregulation of these processes is essential to diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and major psychiatric disorders. Innovative therapeutic approaches, including KRAB- and TET-based repressors, "hit-and-run" epigenome editing, and targeted noncoding RNA regulation, are analyzed alongside translational methodologies that utilize gene therapy vectors, nanoparticle delivery systems, and inducible expression mechanisms. We also examine proof-of-concept studies that demonstrate how to prevent gene expression and alter the transcriptional networks of diseased cells in living organisms. We identify current challenges, including off-target effects, delivery issues, inadequate understanding of long-term stability, and the need for reliable diagnostics, while highlighting the translational promise of combining epigenetic clearance with biogenesis and repair. This review is aimed at providing a comprehensive and critical examination of the molecular principles, therapeutic strategies, and translational obstacles associated with epigenetic editing in neurological and neuropsychiatric disorders, thereby facilitating the development of next-generation precision therapies.},
}

Humans
*Epigenesis, Genetic/genetics
*Gene Editing/methods
*Nervous System Diseases/genetics/therapy
Animals
*Mental Disorders/genetics/therapy
*Genetic Therapy/methods
*Precision Medicine/methods
Epigenome Editing

@article {pmid41455863,
year = {2025},
author = {Elbermawy, Y and El-Desouky, S and Arafa, RK and Elfarrash, S and Bassiouny, A},
title = {Synergistic Neuroprotection in Tauopathic Mice via Green-Synthesized Silver Nanoparticles Co-delivering Methylene Blue and Moringa oleifera.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {331},
pmid = {41455863},
issn = {1559-1182},
mesh = {Animals ; *Methylene Blue/pharmacology/administration & dosage/therapeutic use ; *Moringa oleifera/chemistry ; *Metal Nanoparticles/chemistry/administration & dosage ; *Silver/chemistry/pharmacology ; *Neuroprotective Agents/pharmacology/administration & dosage/therapeutic use ; *Neuroprotection/drug effects ; Mice, Transgenic ; Mice ; *Green Chemistry Technology/methods ; *Tauopathies/drug therapy/pathology/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Plant Extracts/administration & dosage/pharmacology ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options.Most current treatments target only a single pathogenic pathway. We developed an innovative green-synthesized silver nanoparticle formulation for the co-delivery of methylene blue (MB), a tau aggregation inhibitor, and Moringa oleifera (MO) extract, an antioxidant and anti-inflammatory agent. Silver nanoparticles act as multifunctional carriers, improving drug stability and brain delivery, yielding the combined formulation MOMB-Ag-NPs. MOMB-Ag-NPs were synthesized and characterized using ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy-dispersive X-ray (EDX) analysis. Homozygous P301S tau transgenic mice were assigned to four groups: saline (0.9%, i.p.), MB (4 mg/kg/day, i.p.), MO (260 mg/kg/day, oral), or MOMB-Ag-NPs (4 mg/kg/day MB equivalent, i.p.) for 60 days. In vitro GSK-3β inhibition assays and molecular docking analyses assessed mechanistic interactions. Neuroprotective efficacy was evaluated through survival, behavioral tests, immunohistochemistry, ELISA, and Western blotting. MOMB-Ag-NPs displayed spherical morphology (10-25 nm), high stability, and efficient MB encapsulation (EE 54.7%, DL 93.5%). Both MO and MB inhibited GSK-3β in vitro (IC50 = 9.41 and 65.77 µg/mL), corroborated by molecular docking. In vivo, MOMB-Ag-NPs significantly improved locomotor activity, and cognitive performance. Treated mice showed reduced astrogliosis, decreased pro-inflammatory cytokines (TNF-α, IL-6), enhanced autophagy (LC3β), increased antioxidant defenses (SOD), and differential modulation of the AKT/GSK-3β pathway. This study provides novel evidence that a green-synthesized MB and MO nanoformulation exerts synergistic neuroprotective effects in tauopathy mice, highlighting the translational promise of multitarget strategies for AD treatment.},
}

Animals
*Methylene Blue/pharmacology/administration & dosage/therapeutic use
*Moringa oleifera/chemistry
*Metal Nanoparticles/chemistry/administration & dosage
*Silver/chemistry/pharmacology
*Neuroprotective Agents/pharmacology/administration & dosage/therapeutic use
*Neuroprotection/drug effects
Mice, Transgenic
Mice
*Green Chemistry Technology/methods
*Tauopathies/drug therapy/pathology/metabolism
Glycogen Synthase Kinase 3 beta/metabolism
Plant Extracts/administration & dosage/pharmacology
tau Proteins/metabolism

@article {pmid41455134,
year = {2025},
author = {Du, O and Wu, YJ and Li, MY and Du, JR},
title = {The role of HMGB1 in central nervous system (CNS) diseases: mechanisms and therapeutic perspectives.},
journal = {Cytokine},
volume = {198},
number = {},
pages = {157099},
doi = {10.1016/j.cyto.2025.157099},
pmid = {41455134},
issn = {1096-0023},
abstract = {Central nervous system (CNS) diseases represent a major global health burden and are among the leading causes of disability and mortality worldwide. The pathological mechanisms underlying CNS disorders are complex and multifactorial, involving processes such as neuroinflammation, oxidative stress, neuronal damage, and synaptic dysfunction. High-mobility group box 1 (HMGB1), a member of the high-mobility group box (HMGB) protein family, is predominantly localized in the nucleus under physiological conditions, where it contributes to DNA repair, transcriptional regulation, and other cellular functions. However, in various CNS pathologies-including stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), glioblastoma (GBM), epilepsy, depression, multiple sclerosis (MS), and schizophrenia-HMGB1 is released or secreted into the extracellular space. There, it plays a key role in regulating neuroinflammation, cell death, cell migration, and tissue damage and repair, thereby contributing to disease pathogenesis and progression. HMGB1 not only functions as a critical regulator in the progression of CNS diseases but also serves as a biomarker for predicting poor clinical outcomes. Moreover, a growing body of evidence indicates that therapeutic strategies targeting HMGB1 can significantly alleviate pathological damage in various CNS disorders, highlighting its potential as a promising therapeutic target. This review comprehensively summarizes the structure, post-translational modifications, release mechanisms, and receptor systems of HMGB1, along with its roles and mechanisms in CNS diseases. It also discusses the potential of HMGB1 as a biomarker and examines emerging HMGB1-targeted therapeutic strategies, aiming to provide a theoretical foundation for the treatment and drug development of CNS disorders.},
}

@article {pmid41454738,
year = {2025},
author = {Takeda, T and Toritsuka, M and Tamakoshi, H and Iwata, N and Makinodan, M},
title = {Immune involvement in neuropsychiatric disorders: Insights from single-cell transcriptomic studies.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70018},
pmid = {41454738},
issn = {1440-1819},
support = {JPMJMS239F-1-2//Moonshot Research and Development Program/ ; 21gm6310015h0002//Japan Agency for Medical Research and Development/ ; 21uk1024002h0002//Japan Agency for Medical Research and Development/ ; 21wm04250XXs0101//Japan Agency for Medical Research and Development/ ; 22gm1510009h0001//Japan Agency for Medical Research and Development/ ; 24gm1910004s0402//Japan Agency for Medical Research and Development/ ; 24wm0625510h0001//Japan Agency for Medical Research and Development/ ; 23H04173//Japan Society for the Promotion of Science/ ; 24K02386//Japan Society for the Promotion of Science/ ; },
abstract = {Neuropsychiatric disorders pose profound challenges to both research and treatment, largely due to their clinical heterogeneity and the limited understanding of their underlying biological mechanisms. While bulk RNA sequencing (bulk RNA-seq) has been widely used to study gene expression, it cannot resolve cell-type-specific signals or detect rare cellular subpopulations. In contrast, single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) have emerged as transformative technologies, enabling transcriptomic profiling at single-cell resolution. These approaches have revealed immunological alterations across a wide range of disorders. This review introduces recent findings from sc/snRNA-seq studies of immune-related mechanisms in psychiatric disorders-including schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder-as well as in neurological conditions such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple sclerosis, and anti-NMDA receptor encephalitis. While sc/snRNA-seq overcome averaging effects of bulk RNA-seq by resolving cell types, these methods still face challenges. We outline a roadmap that integrates bulk RNA-seq and sc/snRNA-seq to mitigate the remaining gaps.},
}

@article {pmid41454086,
year = {2025},
author = {Mi, X and Shan, K and Ye, X and Cheng, R},
title = {AAD-2004 through clearing H2O2 reduces astrocyte proliferation and promotes neural regeneration after spinal cord injury.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-33322-x},
pmid = {41454086},
issn = {2045-2322},
support = {ZKKY2023003//Zhejiang Medical Association/ ; 2024KY658//Scientific Research Program of Zhejiang Medical Technology/ ; },
abstract = {To assess the effect of AAD-2004 on spinal cord injury (SCI) and to explore its mechanism, we employed an in vitro model using OGD/R-challenged astrocytes to investigate the effects of AAD-2004 against cell death (terminal deoxynucleotidyl transferase dUTP nick-end labeling, tunel), oxidative stress (H2O2 level), and the expression of the key neuroprotective factor MAP2.AAD-2004[2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] is a hydrogen peroxide(H2O2) scavenger primarily used for the treatment of amyotrophic lateral sclerosis and Alzheimer disease that has demonstrated certain neuroprotective properties. In parallel, modified allen's method was adopted, further exploring the potential molecular mechanism in vivo. Based on these conditions, histological and behavioral analysis were performed by Nissl staining, basso mouse scale and footprint analysis. The level of molecules associated with glial scar formation, nerve regeneration, axonal regeneration and H2O2 level were analyzed using western blot, immunofluorescence staining and H2O2 kit. AAD-2004 significantly improved the movement function after SCI and inhibited the proliferation of astrocytes, thus preventing the formation of glial scar by inhibiting of H2O2. At the same time, AAD-2004 promoted nerve regeneration, and the effect was due to neuronal regeneration and axonal regeneration pathways. The expression levels of GFAP and vimentin were significantly downregulated in AAD-2004-treated, and the expression level of Ki67 and PH3 were downregulated. The mean fluorescence intensity of neuronal regeneration (Neun[+]and MAP2[+]) and axonal regeneration-related (NF[+] and GAP43[+]) were significantly upregulated after AAD-2004 treatment. Scavenging H2O2 level is a viable therapeutic strategy, and that AAD-2004 is prospective, and that scavenging H2O2 facilitated nerve regeneration and inhibited glial scar formation for SCI.},
}

@article {pmid41453655,
year = {2025},
author = {Basri, R and Al-Kuraishy, HM and Fawzy, MN and Alruwaili, M and Batiha, GE},
title = {PACAP: A promising disease-modifying target for Alzheimer's disease.},
journal = {Life sciences},
volume = {386},
number = {},
pages = {124176},
doi = {10.1016/j.lfs.2025.124176},
pmid = {41453655},
issn = {1879-0631},
abstract = {Alzheimer's disease (AD) is a significant public health threat, and current therapeutic approaches provide only minimal symptomatic benefit without slowing its progression. This review covers evidence for the expanding involvement of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide with significant and consistent neuroprotective properties in various experimental models of AD. We consolidate evidence that PACAP works via multiple pathways to negate primary pathological events in AD by shifting the metabolism of amyloid precursor protein from the amyloidogenic into non-amyloidogenic, inhibiting tau hyperphosphorylation, controlling neuroinflammation, and promoting synaptic plasticity. The reduced level of PACAP in clinical studies of AD patients supports its therapeutic relevance. Although concerns about PACAP pharmacokinetics and blood-brain barrier (BBB) penetration persist as serious obstacles, recent development of stable analogs and innovative delivery systems holds promise for circumventing these limitations. We also consider how established drugs (metformin, linagliptin, and statins) might provide a degree of neuroprotection in part-seeking through PACAP-related pharmacology. Taken together, the cumulative available evidence places PACAP not only as yet another promising therapeutic candidate but rather as a master regulator of neuroprotection, tackling AD's multifaceted nature. Restoration of PACAP signaling is a very distinct method to intervene in disease development, which offers immeasurable benefit in comparison to symptom relief treatment.},
}

@article {pmid41452714,
year = {2025},
author = {Zhang, J and Zhu, D and Hu, M and Pan, M and Chen, C},
title = {A Combination of Low-Dose Δ[9]-THC and Celecoxib as a Therapeutic Strategy for Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1206},
pmid = {41452714},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly, and no effective therapies are currently available to prevent, treat, or halt its progression. Δ[9]-Tetrahydrocannabinol (Δ[9]-THC), the primary psychoactive compound in marijuana, has been considered a potential therapeutic agent, but clear evidence for its ability to prevent cognitive decline is lacking. Previous studies have demonstrated that Δ[9]-THC-induced cognitive impairments are associated with the induction of cyclooxygenase-2 (COX-2). In this study, we aimed to evaluate whether Δ[9]-THC alone or in combination with Celecoxib, a selective COX-2 inhibitor, could reduce neuropathology and improve cognitive function in AD model animals. We observed that Δ[9]-THC (3.0 mg/kg), either alone or with Celecoxib (1.0 mg/kg), significantly reduced Aβ and tau pathologies, enhanced synaptic marker expression, and prevented the onset of cognitive decline. Notably, the combination treatment produced greater improvements in spatial learning and effectively mitigated Δ[9]-THC-induced neuroinflammatory responses. Furthermore, Δ[9]-THC reversed or attenuated the dysregulated expression of synaptic and immune/inflammation-related genes and restored the downregulated expression of genes linked to AD observed in both AD patients and AD animal models, with greater efficacy when combined with Celecoxib in AD model mice. These findings suggest that the combination of low-dose Δ[9]-THC and Celecoxib holds promise as an early intervention strategy for preventing AD onset or treating mild cognitive impairment (MCI). Importantly, both Δ[9]-THC (in the form of Dronabinol and Nabilone) and Celecoxib are FDA-approved medications already in clinical use, supporting the strong translational potential of this combination therapy and its feasibility for rapid advancement to clinical trials to assess its efficacy in preventing or delaying AD onset in humans.},
}

@article {pmid41452429,
year = {2025},
author = {Heidari, Z and Zakaee, A and Vafadar, A and Alavimanesh, S and Charami, H and Jamali, Z and Jahromi, AH and Rakhsha, A and Savardashtaki, A},
title = {An overview of gene and cell therapy approaches for Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {10},
pmid = {41452429},
issn = {1573-7365},
mesh = {*Alzheimer Disease/therapy/genetics ; Humans ; *Genetic Therapy/methods ; *Cell- and Tissue-Based Therapy/methods ; Animals ; },
abstract = {Alzheimer's disease (AD), acknowledged as the leading cause of dementia, is defined by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs) in the brain. This condition presents a significant challenge to global health due to its complex and multifaceted characteristics. Pharmacological treatments for AD mainly focus on relieving symptoms instead of addressing the fundamental progression of the condition. Currently, there are three cholinesterase inhibitors (ChEIs) that can be used for the treatment of AD: donepezil, rivastigmine, and galantamine, along with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. Although these medications can improve cognitive function and assist patients in their daily activities, it is crucial to understand that they do not halt the progression of the disease itself. Recently, innovative therapeutic strategies have been introduced for the treatment of this disease. Cell and gene therapies hold remarkable potential for the treatment of AD. Gene therapy, in particular, enables the precise modulation of AD-related genes, enhances neuroprotective factors, and mitigates the accumulation of amyloid plaques. Additionally, cell-based therapies utilizing mesenchymal stromal cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) are designed to replace lost neurons, modulate immune responses, and restore functional neural networks. Together, these innovative techniques represent significant advancement in the treatment of AD, instilling hope for enhanced patient outcomes and a higher quality of life. In this review, we emphasize the innovative cell and gene strategies, along with in vitro and preclinical studies, that explore the potential of gene and cell-based therapies as treatments for AD.},
}

*Alzheimer Disease/therapy/genetics
Humans
*Genetic Therapy/methods
*Cell- and Tissue-Based Therapy/methods
Animals

@article {pmid41452267,
year = {2025},
author = {Cai, X and Huang, Y and Wang, T and Gao, J and Tang, Y and Zhu, C and Rong, S},
title = {Mesoporous PdPt Nanozymes with Target Peptides and Cascade Reactive Oxygen Species Scavenging for Boosting Alzheimer's Disease Treatment.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.5c17413},
pmid = {41452267},
issn = {1936-086X},
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disease that has become a major health problem nowadays. Inhibiting the aggregation of amyloid-β (Aβ) peptides has made progress in AD treatments. Here, we synthesized mesoporous PdPt nanozymes to immobilize target peptide KLVFFAED for high-efficiency AD treatment. Thanks to the high surface area of the mesoporous nanospherical structure of PdPt nanozymes, lots of KLVFFAED were grafted with a concentration as high as 439.2 μg mL[-1], amplifying inhibition activity against Aβ aggregations. Importantly, the system has a pre-eminent photothermal property in the near-infrared region and exhibits the ability to photothermally disintegrate Aβ aggregates. Moreover, the integrated superoxide dismutase/catalase mimetic activity of PdPt nanozymes also achieves cascade reactive oxygen species (ROS) scavenging to alleviate oxidative stress and neuroglial damage, thus delaying the progression of AD. Therefore, the designed system can simultaneously block Aβ aggregation, destabilize Aβ fibrils, and clear ROS, which together enhance the therapeutic effects, providing important insights into the applications of nanozymes for AD therapy.},
}

@article {pmid41451887,
year = {2025},
author = {Lynch, SY and Jia, J and Miles, N and Boiser, J and Buhl, DL and Graff, O and Zadikoff, C},
title = {ABBV-552 in patients with mild Alzheimer's disease: a randomized phase IIb trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e70994},
pmid = {41451887},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Double-Blind Method ; Treatment Outcome ; Dose-Response Relationship, Drug ; Mental Status and Dementia Tests ; },
abstract = {INTRODUCTION: This proof-of-concept, dose-finding phase IIb trial evaluated treatment with ABBV-552 compared with placebo in participants with clinically diagnosed mild Alzheimer's disease (AD).

METHODS: Participants aged 50 to 90 years with a Mini-Mental State Examination score of 20 to 26 and a global Clinical Dementia Rating score of 0.5 to 1.0 were randomized 1:1:1:1 to placebo or ABBV-552 (1, 5, or 15 mg) daily. The primary endpoint was the change from baseline in the 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 14) at week 12.

RESULTS: Two hundred sixty-three participants were randomized. The least-squares mean difference (vs placebo) in change from baseline at week 12 in ADAS-Cog 14 total score (95% confidence interval) for ABBV-552 1 mg was -0.02 (-1.87, 1.83), nominal p = 0.9819; 5 mg, -0.42 (-2.25, 1.42), nominal p = 0.6545; 15 mg, 0.25 (-1.58, 2.08), nominal p = 0.7860. Treatment-emergent adverse events occurred in 48.5% of ABBV-552 recipients versus 42.2% in the placebo group; no safety concerns were identified.

DISCUSSION: ABBV-552 did not demonstrate a meaningful difference versus placebo on the primary endpoint.

HIGHLIGHTS: ABBV-552 is a small molecule that modulates the SV2A receptor in neurons ABBV-552 may enhance synaptic efficiency leading to improved cognition in patients with Alzheimer's disease (AD) Participants with mild AD were treated with either placebo, 1 mg, 5 mg, or 15 mg of ABBV-552 covering an estimated 35% to 80% SV2A receptor occupancy in a phase II randomized clinical trial Results failed to show efficacy over placebo as measured by ADAS-Cog 14 at week 12 ABBV-552 was generally safe and well tolerated.},
}

Humans
*Alzheimer Disease/drug therapy
Male
Aged
Female
Middle Aged
Aged, 80 and over
Double-Blind Method
Treatment Outcome
Dose-Response Relationship, Drug
Mental Status and Dementia Tests

@article {pmid41451871,
year = {2025},
author = {Yang, T and Huhe, H and Williams, SP and Kaur, S and Ay, YA and Davis-Gilbert, ZW and Cary, GA and Paisie, C and Butler, RR and Wiley, J and Betarbet, R and Fu, H and Duong, D and Seyfried, NT and Leal, K and Carter, GW and Edwards, A and Levey, AI and Capener, JL and Drewry, DH and Hossain, MA and Oh, HJ and Axtman, AD and Sukoff Rizzo, SJ and Longo, FM and , },
title = {PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {12},
pages = {e71033},
pmid = {41451871},
issn = {1552-5279},
support = {//PhRMA Foundation/ ; //The SGC is a registered charity that receives funds from Bayer AG, Boehringer Ingelheim/ ; //NIH grants NIA U54AG065187/ ; //Applebaum Foundation Fund/ ; //Archer Fund/ ; //Jean Perkins Foundation/ ; },
mesh = {Animals ; *Dendritic Spines/drug effects/pathology/metabolism ; *p21-Activated Kinases/antagonists & inhibitors/metabolism ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice, Transgenic ; *Alzheimer Disease/pathology/metabolism/drug therapy ; *Neurons/drug effects/metabolism ; Hippocampus/drug effects/pathology ; Disease Models, Animal ; Mice ; Female ; Humans ; Dibenzazepines ; Pyrrolidines ; },
abstract = {INTRODUCTION: Synaptic spine loss in Alzheimer's disease (AD) contributes to cognitive decline. p21-activated kinase 1 (PAK1), a regulator of spine integrity, is aberrantly activated in AD. We investigated whether PAK1 inhibition might preserve dendritic spines in vitro and in vivo.

METHODS: Oligomeric amyloid beta (oAβ) or tau (oTau) were applied to hippocampal neurons ± NVS-PAK1-1, a selective PAK1 inhibitor. NVS-PAK1-1 was orally administered to 5xFAD mice. The effects of NVS-PAK1-1 treatment on PAK1 activity, spine density, and the proteome were assessed using phospho-PAK1 (pPAK1) western blotting, Golgi staining, and mass spectrometry for proteomic analyses.

RESULTS: NVS-PAK1-1 prevented oAβ and oTau-induced spine loss in vitro. In 5xFAD mice, NVS-PAK1-1 demonstrated brain exposure after oral administration and reduced PAK1 activation, prevented spine loss, and partially normalized synaptic proteomic signatures in females in absence of alterations in brain or plasma Aβ.

DISCUSSION: PAK1 inhibition enhances spine resilience in AD models, supporting its therapeutic potential.

HIGHLIGHTS: p21-activated kinase 1 (PAK1) inhibitors prevent oligomeric amyloid beta (oAβ) and oligomeric tau-induced spine loss and dendritic degeneration in cultured mouse hippocampal neurons. NVS-PAK1-1, a selective PAK1 inhibitor, protects against oAβ-induced spine loss in a dose-dependent manner (EC50 = 2 nM). Oral administration of NVS-PAK1-1 achieves brain penetration and bioavailability in normal CD-1 mice, and target engagement in 5xFAD mice. Chronic NVS-PAK1-1 treatment mitigates spine loss in the somatosensory cortex of 6-month-old 5xFAD female mice. Chronic treatment with NVS-PAK1-1 restores proteomic abundance of actin cytoskeleton and dendritic spine-associated proteins, including cofilin 2 and pyruvate dehydrogenase kinases, downstream of PAK1 in young 5xFAD female mice showing spine resilience. Clinical oncology trials with other PAK1 inhibitors support potential repurposing or novel compound development for Alzheimer's disease trials.},
}

Animals
*Dendritic Spines/drug effects/pathology/metabolism
*p21-Activated Kinases/antagonists & inhibitors/metabolism
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism/toxicity
Mice, Transgenic
*Alzheimer Disease/pathology/metabolism/drug therapy
*Neurons/drug effects/metabolism
Hippocampus/drug effects/pathology
Disease Models, Animal
Mice
Female
Humans
Dibenzazepines
Pyrrolidines

@article {pmid41451412,
year = {2025},
author = {Li, S and Qian, W and Zhang, Z and Chen, Y and Hou, X and Min, B and Zhou, H and Zhu, X and Ling, J and Yang, W and Cao, S},
title = {Comprehensive safety assessment of donepezil: pharmacovigilance analysis based on the FDA adverse event reporting system.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1655216},
pmid = {41451412},
issn = {1664-2295},
abstract = {BACKGROUND: Alzheimer's disease (AD) has a growing global prevalence, and the need for safe and effective treatments is urgent. Donepezil is commonly used therapeutic agents for AD but has safety controversies. The objective of this study was to thoroughly evaluate donepezil's adverse event profile using actual data.

METHODS: In this study, reports of donepezil-related adverse events were collected from the first quarter of 2004 to the fourth quarter of 2024 through the FAERS database. The association of donepezil-induced adverse events was disproportionality analyzed using Reporting odds Ratios (ROR) and Proportional Reporting Ratio (PRR) and Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS), among other methods.

RESULTS: A total of 26,120 ADRs with donepezil as the "first suspect" were retrieved during the reporting period. The most common AEs included nausea, vomiting, syncope, and dizziness, which were consistent with the labeling of the medication and clinical trials. Unintended major AEs such as fall, hypotension, tremor, cognitive disorder, mania, and the highest signal of pleurothotonus were also detected. The reports also collected were characterized by a high proportion of female patients (51.3%) and the time of AE induction within 30 days (41%).

CONCLUSION: Donepezil treatment needs to focus on cardiovascular and neurological adverse events, especially for women, elderly patients, or patients with co-morbidities, cardiac monitoring and dose adjustment should be strengthened. Clinics need to balance efficacy and risk, develop individualized dosing regimens, and explore novel therapeutic strategies to improve long-term safety.},
}

@article {pmid41450657,
year = {2025},
author = {Zhao, Y and Xi, E and Wang, Z and Gao, N and Sun, H and Zhu, G},
title = {Nanoamplifier Agents Transiently Rise the Metabolism of β‑Amyloid Peptide in Urine for the Early Diagnosis of Alzheimer's Disease.},
journal = {JACS Au},
volume = {5},
number = {12},
pages = {6169-6178},
pmid = {41450657},
issn = {2691-3704},
abstract = {Alzheimer's disease (AD) is the most common form of dementia without effective treatment. Therefore, early diagnosis for timely treatment and delayof the onset of AD are critical. At present, detecting β-amyloid (Aβ) in cerebrospinal fluid is still the most important clinical method. However, the invasive detection method is harmful and difficult to promote. Recent research has shown that Aβ was found not only in blood and cerebrospinal fluid, but also in urine, which could be used for noninvasive testing. Compared with blood/cerebrospinal fluid, the background proteins in urine are very low, but unfortunately the content of Aβ is even lower. Therefore, if the concentration of Aβ is increased with the background proteins maintained at the low level, urine could be an ideal noninvasive early detection target for AD. Gold nanoparticles (AuNP) with ultrasmall size (<6 nm) could be rapidly metabolized by the kidneys and excreted with urine, and easily regulated by the metabolic pathway between kidneys and liver by changing their size. After screening, we found 3 nm AuNP had the highest renal metabolic efficiency, and by modifying with kidney targeting peptides and Aβ antibody 6E10, the complex system (P6-Au) acted as a "Aβ-targeting renal metabolic carrier", which both metabolized rapidly through the kidneys and increased the concentration of Aβ in urine. After tail vein injection of P6-Au, the Aβ content in the urine of 5×FAD transgenic mice increased by more than 20 times within the next 24 h, which resulted in the diagnosis time being advanced from the ninth month to the fifth month and provided a new approach for early detection of AD.},
}

@article {pmid41450541,
year = {2025},
author = {Chen, C and Shao, Q and Zhou, S},
title = {Exploring the Mahuang Fuzi Xixin Decoction's mechanism for treating Alzheimer's disease using molecular docking and network pharmacology.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1688316},
pmid = {41450541},
issn = {1663-4365},
abstract = {OBJECTIVE: Explore the potential mechanism of Mahuang Fuzi Xixin Decoction (MFXD) in the treatment of Alzheimer's disease (AD) using network pharmacology, molecular docking approaches, and test its efficacy by in vitro experiments.

METHODS: Active components of MFXD were screened from TCMSP, BATMAN-TCM, and TCMID, with corresponding targets obtained from SwissTargetPrediction and TCMSP. AD-related differential genes were retrieved from GEO. Intersection targets were identified via Venn diagrams, followed by GO/KEGG enrichment analyses, PPI network construction, and molecular docking. In vitro validation experiments were carried out using PC12 cells induced by Aβ25-35 to simulate the pathological state of AD. For the detection of cell viability, the CCK-8 assay was employed to evaluate the protective effect of MFXD and its active components on damaged PC12 cells. Western blot analysis was used to determine the protein expression levels of key molecules involved in AD-related signaling pathways, including phosphorylated p-NF-κB p65, NF-κB p65, p-GSK-3β, GSK-3β, MMP-9, p-Tau, and Tau. Additionally, the ELISA was utilized to measure the secretion level of TNF-α in the supernatant of Aβ25-35-induced PC12 cells, so as to assess the anti-inflammatory effect of MFXD.

RESULTS: Thirty-seven active components and 230 targets of MFXD were identified, along with 4913 AD-related differentially expressed genes from GEO dataset GSE122063, yielding 47 intersection targets. GO annotation enriched these targets in processes like reactive oxygen species metabolism, components like extracellular matrix, and functions like neurotransmitter binding; several pathways were enriched in the KEGG analysis, such as TNF signaling pathway, calcium signaling pathway, and NF-κB signaling pathway. The intersection target PPI network identified MMP9, EGFR, FOS as core targets. Molecular docking results indicated that quercetin binds to the three core targets (MMP9, EGFR, FOS), while luteolin binds preferentially to EGFR and MMP9. In vitro, Aβ25-35-induced PC12 cells treated with quercetin/luteolin had concentration-dependent viability increases (all P < 0.001); 15% MFXD-containing serum restored viability to ≥ 95% (P < 0.001 vs. AD model, comparable to DHCL). Western blot showed AD model had elevated p-NF-κB p65/NF-κB p65, MMP9/β-actin, p-Tau/Tau and reduced p-GSK-3β/GSK-3β (all P < 0.05); MFXD reversed these (all P < 0.05), while DHCL only inhibited p-NF-κB p65/NF-κB p65. ELISA showed MFXD and DHCL both reduced AD model's TNF-α (all P < 0.001).

CONCLUSION: MFXD potentially exerts anti-AD effects through a multi-component, multi-target, multi-pathway approach. Its key active components (quercetin, luteolin) may act by modulating the core target MMP9. Also, MFXD can simultaneously regulate several pathways, such as the TNF signaling pathway, Calcium signaling pathway, and NF-κB signaling pathway, and target Tau protein-related pathology by restoring the phosphorylation level of GSK-3β to suppress abnormal hyperphosphorylation of Tau, and thereby alleviating pathological damage in AD.},
}

@article {pmid41449667,
year = {2025},
author = {Günaydin, C and Hackett, NR and Wakim, V and Sondhi, D and Kaminsky, SM and Crystal, RG},
title = {Prime Editing of Alzheimer's Disease High-Risk APOE4 Allele by Brain-Directed Adeno-Associated Virus Vectors.},
journal = {Human gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.1177/10430342251401888},
pmid = {41449667},
issn = {1557-7422},
abstract = {Common variants of the apolipoprotein E (APOE) gene have a major impact on the risk of developing Alzheimer's disease (AD). Relative to homozygotes with the common E3 allele, the APOE4 variant (C112R) increases risk by 3.5-fold in E3/E4 heterozygotes and 15-fold in E4 homozygotes. Since the E3 and E4 alleles differ only by a single nucleotide, gene editing of E4 to E3 is a potential strategy to reduce AD risk in E4 homozygotes. Because the APOE pool in the brain is separate from systemic APOE, editing to treat AD would ideally be directed to the brain. Following in vitro optimization of prime editing guide RNAs, efficient prime editing expression cassettes were inserted into the adeno-associated virus (AAV) split-intein system and packaged into pairs of AAV vectors for in vivo editing. The AAV vectors were administered to human homozygous APOE4-targeted replacement mice (TRE4), and APOE4 to APOE3 editing efficiency was assessed after 4 weeks. The prime editing construct designated APOE3/4-3_10 was the most efficient at APOE4 to APOE3 conversion, both in liver following intravenous delivery and in brain following intrahippocampal delivery. To assess brain-wide editing, two AAV capsids were compared, including AAVrh.10 with administration either directly to the hippocampus or to the cerebrospinal fluid via the cisterna magna and AAV-CAP.B10 administered intravenously. Other than minor differences in APOE4/3-3_10 mediated E4 to E3 editing in the cerebellum, the different capsids and routes yielded similar editing efficacy throughout the brain. This may represent a candidate treatment to reduce the risk of AD.},
}

@article {pmid41448751,
year = {2025},
author = {Liu, S and Wang, L and Li, S and Xu, G},
title = {[Effects of 40 Hz light flicker stimulation on hippocampal-prefrontal neural activity characteristics during working memory tasks in Alzheimer's disease model rats].},
journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi},
volume = {42},
number = {6},
pages = {1107-1114},
pmid = {41448751},
issn = {1001-5515},
mesh = {Animals ; *Alzheimer Disease/physiopathology/therapy ; *Memory, Short-Term/physiology/radiation effects ; *Prefrontal Cortex/physiopathology ; *Hippocampus/physiopathology/physiology ; Rats, Wistar ; Rats ; Disease Models, Animal ; Male ; *Photic Stimulation ; Maze Learning ; },
abstract = {40 Hz light flicker stimulation is deemed to hold considerable promise in the treatment of Alzheimer's disease (AD). However, whether its long-term effect can improve working memory and its related mechanisms remains to be further explored. In this study, 21 adult Wistar rats were randomly divided into the AD light-stimulation group, the AD group and the control group. AD models were established in the first two of these groups, with the light-stimulation group receiving long-term 40 Hz light flicker stimulation. Working memory performance across groups was subsequently evaluated using the T-maze task. To investigate the potential neural mechanisms underlying the effects of 40 Hz light stimulation on working memory, we examined changes in neuronal excitability within the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as alterations in inter-regional synchronization of neural activity. The findings demonstrated that prolonged 40 Hz light stimulation significantly improved working memory performance in AD model rats. Furthermore, the intervention enhanced the synchronization of neural activity between the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as the efficiency of information transfer, primarily mediated by theta and low-frequency gamma oscillations. This study provides theoretical support for exploring the mechanisms of 40 Hz light flicker stimulation and its further clinical application in the prevention and treatment of Alzheimer's disease.},
}

Animals
*Alzheimer Disease/physiopathology/therapy
*Memory, Short-Term/physiology/radiation effects
*Prefrontal Cortex/physiopathology
*Hippocampus/physiopathology/physiology
Rats, Wistar
Rats
Disease Models, Animal
Male
*Photic Stimulation
Maze Learning

@article {pmid41448509,
year = {2025},
author = {Kim, N and Jeon, JY and Seo, J and Lee, Y and Kim, HJ and Kim, JS},
title = {A Combined Model of Convolutional Neural Networks and Graph Attention Networks for Improved Classification of Mild Cognitive Impairment.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121674},
doi = {10.1016/j.neuroimage.2025.121674},
pmid = {41448509},
issn = {1095-9572},
abstract = {Mild cognitive impairment (MCI), a precursor of Alzheimer's disease (AD), underscores the importance of early diagnosis and treatment. With an aging global population, AD prevalence is rising, necessitating more precise diagnostic methods. Deep learning technology shows promise for MCI and AD classification, but existing convolutional neural network (CNN) and graph attention network (GAT) models have limitations in capturing brain structural features and detecting microlesions. To address these issues, we propose a novel approach combining a CNN and modified GAT model to improve MCI classification. Magnetic resonance imaging volume data were analyzed using a CNN, whereas cortical thickness data were modeled using a GAT, leveraging their complementary strengths. Preprocessing involved extracting brain's structural features via the CIVET pipeline, and t-SNE was used to visualize the data's high-dimensional distribution. Final classification was performed using a multilayer perceptron, integrating feature vectors from both models. Performance evaluation metrics included the area under the curve (AUC), F1-score, sensitivity, and specificity. The combined CNN-GAT model outperformed existing single-model approaches, particularly in MCI classification, effectively distinguishing subtle variations between normal aging and MCI. The combined CNN-GAT model improved MCI classification performance by addressing the limitations of existing approaches. By capturing brain structural features and inter-regional relationships, it offers significant potential for advancing early diagnosis and treatment strategies for neurodegenerative diseases. Future efforts will focus on enhancing performance through additional data optimization.},
}

@article {pmid41447429,
year = {2025},
author = {Chandrasekaran, A and Malek-Ahmadi, M and Decourt, B and Sabbagh, MN},
title = {Informant-Based Questionnaires in the Diagnostic Pathway for Screening of Cognitive Impairment.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41447429},
issn = {2193-8253},
abstract = {Alzheimer's disease (AD) remains the most common form of dementia in elderly populations. Accurately diagnosing early forms of dementia and AD remains a significant clinical challenge, especially in fast-paced primary care settings. Informant-based questionnaires that rely on close caregivers of the patients, such as the Informant Questionnaire on Cognitive Decline in the Elderly, the Ascertain Dementia 8-Item, the Quick Dementia Rating System, and the Alzheimer's Questionnaire, have recently been shown to be a valuable supplement to current standards of diagnosis, such as performance-based tests. This review aimed to explore the key characteristics of various informant-based questionnaires and evaluate their efficacy in the medical setting. Analysis of each test demonstrated that informant-based assessments show a strong ability to detect cognitive impairment early on in its pathology and can highlight gradual decline over time, compared with the single-timeframe evaluations that performance-based tests provide. Informant-based questionnaires are also able to circumvent challenges associated with the patient's education level, language, and other cultural biases, thus making them useful in diverse populations. When used in conjunction with performance tests, informant-based tests can significantly streamline the diagnostic process for dementia and enhance management and treatment strategies. Further research is advised to effectively integrate these tests into routine clinical practice and establish a new standard of care.},
}

@article {pmid41446880,
year = {2025},
author = {van Brummelen, R and van Brummelen, AC},
title = {The role of neuro-supportive substances of natural origin in neurological conditions-A literature-based formulators' perspective.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1647092},
pmid = {41446880},
issn = {1664-2295},
abstract = {Products of natural origin are seldom tested up to a point of full acceptance, mainly due to a lack of financial viability for commercialization. Yet many come with a rich history of use and proof of concept testing. We investigated literature regarding the possible role and function of the best known of these nutraceuticals in relationship to three neurological conditions i.e. stroke, Alzheimer's - (AD) and Parkinson's disease (PD), and their potential as supportive therapies. Current studies suggest that citicoline has a neuroprotective effect in ischemic conditions, playing a role in the restoration of the barrier function of endothelial cells, activating repair mechanisms and possibly decreasing ischemic lesion size in stroke, as well as increasing dopamine availability in PD. Citicoline was also demonstrated to increase the levels of sirtuin 1 (SIRT1), thus reducing inflammation-leading to improved cognitive status and a better quality of life in cognitive impairment. N-Acetylcysteine (NAC) shows pro-cognitive effects, increasing glutathione (GSH) levels that are decreased in AD and PD patients, possibly decreasing neuroinflammation. Mechanistic studies indicate the potential neuroprotective and neurorestorative effects of resveratrol by its anti-inflammatory and anti-apoptotic activity, also increasing SIRT1 levels and promoting the outgrowth of neurite protrusions and synaptogenesis. Curcumin's anti-inflammatory effects via inhibition of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can potentially delay progression of PD. Some nutraceuticals, e.g., citicoline, show synergism in combination with current therapies. We propose a renewed, risk-benefit approach for inclusion of the investigated nutraceuticals with limited indications in certain neurological treatment regimens.},
}

@article {pmid41446876,
year = {2025},
author = {Sun, Y and Chen, D and Ye, Q and You, Z and Zhao, Z and Shi, J and Sun, H and Li, S and Xu, X and Xu, Y and Zhang, P and Tang, Z},
title = {Applications of Endovascular Brain-Computer Interface in Patients with Alzheimer's Disease.},
journal = {Research (Washington, D.C.)},
volume = {8},
number = {},
pages = {1049},
pmid = {41446876},
issn = {2639-5274},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly, leading to important impairments in cognitive function and the ability to live independently. This results in substantial disability and places an increasing burden on families and society. Currently, the therapeutic approaches adopted in clinical practice predominantly hinge upon cholinesterase inhibitors and the N-methyl-d-aspartate (NMDA) receptor antagonist memantine. Nevertheless, these medications merely alleviate symptoms and fail to tackle the pathological characteristics of AD. In recent years, monoclonal antibodies such as lecanemab and donanemab against β-amyloid (Aβ) have shown good efficacy in clinical practice for early-stage AD patients. However, the early diagnosis of AD remains a challenge. Against this backdrop, endovascular brain-computer interface (EBCI) offers an integrated solution for the early diagnosis and neuroregulatory treatment of AD patients, with minimal invasiveness. This review comprehensively examines the safety and feasibility of EBCI for AD patients, focusing on 3 major application areas: early diagnosis, deep brain stimulation targeting specific brain regions, such as the fornix and the basal nuclei of Meynert, and the use of external neurofeedback devices. Furthermore, we explore future development trends in this field, including miniaturization, integration, and the exploration of deep brain regions.},
}

@article {pmid41446471,
year = {2025},
author = {Masna, H and Konda, M and Ganti, L},
title = {Huntington's Disease Research Over Six Decades: Global Insights, Gaps, and Future Directions.},
journal = {Cureus},
volume = {17},
number = {11},
pages = {e97567},
pmid = {41446471},
issn = {2168-8184},
abstract = {Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the huntingtin (HTT) gene. It leads to progressive decline in motor function, cognition, and behavior, often following a prolonged pre-symptomatic phase. Although research on HD has progressed, significant gaps remain in understanding its full impact, particularly in areas such as mental health, global collaboration, and early intervention. A bibliometric analysis was conducted using the Web of Science Core Collection to evaluate global research trends in HD and its testing from 1966 to 2025. A total of 1,515 publications were analyzed for authorship patterns, contributing countries, journal sources, and frequently occurring keywords. VOSviewer software v1.6.15 (Centre for Science and Technology Studies, Leiden University, The Netherlands) was used to visualize author networks and keyword co-occurrence. Publication activity peaked in 2014 and 2018, with 101 and 96 articles published, respectively. The United States emerged as the leading contributor to HD research, followed by European countries with fewer publications. Keyword analysis revealed strong associations between HD and other neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, as well as recurring terms related to genetic testing, brain anatomy, and animal models. Limited author collaboration was observed, with only a few dense research clusters present. This analysis highlights the growing body of research on HD, particularly in genetic mechanisms and therapeutic modeling. However, the concentration of research within a few countries and author groups suggests limited global collaboration. Emerging gaps include underrepresentation of mental health impacts, disparities in geographic research output, and narrow journal dissemination. Strengthening international cooperation and diversifying research focus could accelerate progress in diagnosis, treatment, and overall patient care.},
}

@article {pmid41446236,
year = {2025},
author = {Fredriksen, K and Joshi, SS and Chang, A and Li, L},
title = {High-density lipoprotein mimetic peptide 4F ameliorates APOE4-associated lipid dysfunction in primary and iPSC-derived astrocytes and cerebral organoids.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.16.694774},
pmid = {41446236},
issn = {2692-8205},
abstract = {APOE is the greatest genetic risk factor for late-onset Alzheimer's disease (AD). In humans, APOE has three isoforms: APOE2 (E2), APOE3 (E3), and APOE4 (E4); E4 increases AD risk, while E3 is neutral and E2 decreases risk. In the brain, APOE is predominantly produced by astrocytes, where it binds lipids to form HDL-like particles, and plays a central role in lipid homeostasis, Aβ clearance, and neuroimmune modulation. Its lipidation state is critical for function, with E4 being poorly lipidated compared to E2 and E3, contributing to the pathogenic effects of E4 while also offering a potential therapeutic target. We have previously demonstrated that the HDL-mimetic peptide 4F increases APOE secretion and lipidation in wild-type mouse astrocytes and counteracts the inhibitory effects of Aβ42. Here, we assessed the ability of 4F to mitigate E4-associated dysfunction using primary astrocytes from humanized E3 and E4 knock-in mice and isogenic human iPSC-derived astrocytes and cerebral organoids. Results showed that 4F enhanced APOE secretion and lipidation in both cellular and organoid models in the absence or presence of aggregated Aβ42. Compared to E3 astrocytes, E4 astrocytes were prone to Aβ42-induced inhibition of APOE secretion and lipidation and increased accumulation of lipid droplets. 4F treatment ameliorated the inhibitory effects of Aβ42 and reduced lipid droplet accumulation. These findings support the therapeutic potential of HDL-mimetic peptides for E4-associated dysfunction in AD.},
}

@article {pmid41446123,
year = {2025},
author = {Shao, B and Kula, B and Le, H and Venkhatesh, P and Katti, P and Marshall, AG and Chittaranjan, S and Thapilyal, S and Kalpana, NH and Nivedya, C and Roszczyk, A and Mobley, H and Killion, M and St John, E and Martin, P and Rodrigiuez, B and Hamilton, M and Bell, L and Wyckoff, SM and Moran, LA and Philips, M and Hubert, D and Tomeau, B and Afolabi, JM and Kirabo, A and Blanco, I and Reasonover, S and Drake, LE and Lippmann, ES and Evans, C and Santisteban, MM and Cheairs, TG and Mesenga, S and Wanjalla, C and Gaddy, J and McMillan, R and Perez, CPH and Paing, HH and Schafer, JC and Mobley, B and Berry, J and Crabtree, A and Kovtun, O and Goodwin, S and Lopez, EG and Dash, C and Dai, DF and Miller-Fleming, TW and Hinton, A and Smith, NA},
title = {The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.13.693635},
pmid = {41446123},
issn = {2692-8205},
abstract = {Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD. Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.},
}

@article {pmid41445693,
year = {2025},
author = {Lee, S and Yin, L and Teopiz, KM and Wong, S and Han Le, G and Xiao, N and Stahl, S and Valentino, K and Ho, R and Zhang, MC and Greg Rhee, T and McIntyre, RS},
title = {Effects of glucagon-like peptide-1 receptor agonists on psychiatric disorders: a systematic review.},
journal = {Therapeutic advances in psychopharmacology},
volume = {15},
number = {},
pages = {20451253251396304},
pmid = {41445693},
issn = {2045-1253},
abstract = {Extant literature pertaining to the administration of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for Alzheimer's disease, Parkinson's disease, major depressive disorder, bipolar disorder, substance-, alcohol- and nicotine-use disorders, suggests promising efficacy beyond the current FDA-approved indications (e.g., type 2 diabetes mellitus, obesity). The implicated brain regions of the aforementioned mental disorders contain glucagon-like peptide 1 (GLP-1) receptors associated with improving cognitive and behavioral functioning. Therefore, we aimed to systematically review the treatment effects of GLP-1RAs in various neurocognitive and psychiatric disorders. Online databases including PubMed, OVID, MEDLINE, Embase, PsycINFO and Google Scholar, were searched from inception until October 1, 2024. Additional studies were identified from the reference lists of the included articles. 22 studies were identified, with a total of 186,847 participants included. Results reported that GLP-1RAs meaningfully improved cognitive and affective functioning (e.g., memory), which in some cases was sustained beyond exposure to the agent. Separately, multiple epidemiological studies reported that GLP-1RAs have protective effects, with a suggestion of decrease in the incidence of mental disorders. These results provides the impetus for large, long-term, randomized controlled trials for GLP-1 RAs for the treatment of various mental disorders. This review is not registered in PROSPERO or any other registry.},
}

@article {pmid41445644,
year = {2025},
author = {Li, R and Langford, O and Insel, PS and Sperling, RA and Raman, R and Aisen, PS and Donohue, MC},
title = {Divergent latent classes of cognitive decline in the A4 and LEARN studies.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.15.25342305},
pmid = {41445644},
abstract = {IMPORTANCE: Alzheimer disease biomarkers in cognitively unimpaired older adults are associated with later cognitive and clinical decline, yet substantial heterogeneity in the timing and rate of decline remains insufficiently characterized.

OBJECTIVE: To identify subgroups of cognitive decline among biomarker-defined cognitively unimpaired adults and determine baseline predictors of heterogeneity in preclinical Alzheimer disease progression.

Longitudinal data were drawn from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study, which enrolled amyloid-positive participants, and the parallel LEARN Study, which enrolled amyloid-negative individuals meeting all other A4 criteria. Participants completed baseline amyloid PET, plasma P-tau217, structural MRI, and serial cognitive assessments. Latent Class Mixed-Effects Models (LCMMs) were used to identify distinct cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker characteristics were evaluated.

MAIN OUTCOMES AND MEASURES: The primary outcome was longitudinal change in the Preclinical Alzheimer's Cognitive Composite (PACC).

RESULTS: Three cognitive trajectory classes were identified: stable, slow decliners, and fast decliners. Higher plasma P-tau217, smaller hippocampal volume, and elevated tau PET were associated with greater odds of belonging to declining classes. Among amyloid-positive individuals, approximately 70% were classified as stable over the observed follow-up interval.

CONCLUSIONS AND RELEVANCE: Latent class modeling reveals marked heterogeneity in preclinical cognitive trajectories, even among individuals with biomarker evidence of Alzheimer pathology. The high proportion of stable individuals is consistent with the long presymptomatic interval. Identifying subgroups of decline may improve prognostic modeling and guide enrichment strategies for precision secondary prevention trials.},
}

@article {pmid41444683,
year = {2025},
author = {Weissmann, C and Castellanos, LCS and Montes, MM and Uruk, G and Youssef, H and Reichard, RR and Gatto, RG and Josephs, KA},
title = {4R-tau isoform induction via TDP-43 in neurons in response to insulin: converging signaling pathways with implications for neurodegenerative disease.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {258},
pmid = {41444683},
issn = {2051-5960},
support = {PIP Grant No. 11220210100589CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; UBACYT (Grant No. 20020220400291BA)//Universidad de Buenos Aires/ ; R01-AG37491//National Institute for Health Care Management Foundation/ ; R01 AG037491/AG/NIA NIH HHS/United States ; PICT 2020-01211//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; },
mesh = {Animals ; *tau Proteins/metabolism ; *DNA-Binding Proteins/metabolism ; *Neurons/metabolism/drug effects ; Humans ; *Signal Transduction/drug effects/physiology ; *Insulin/pharmacology ; Protein Isoforms/metabolism ; HEK293 Cells ; Mice ; *Neurodegenerative Diseases/metabolism ; Phosphorylation/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology/metabolism ; Mice, Inbred C57BL ; },
abstract = {Tau protein isoforms, regulated during development, are influenced by the nuclear factor TDP-43, which plays a crucial role in tau mRNA stability and exon 10 inclusion. Both tau and TDP-43 are prone to pathological phosphorylation and aggregation, with specific phosphorylated forms of TDP-43 linked to cytoplasmic mislocalization and alterations in the 3R/4R tau ratio as detected in different pathologies. In this study, we show that insulin treatment of embryonic mouse primary cortical neurons-cells that normally express only 3R-tau-induces the expression of 4R-tau, suggesting that metabolic signaling can influence tau isoform expression in a developmentally immature neuronal context. In addition, experiments in HEK293 cells revealed isoform-specific stabilization effects and showed that insulin promotes TDP-43 redistribution to the cytoplasm along with a phosphorylation pattern. These results underscore the complex interplay between TDP-43 and tau isoforms and metabolic signaling pathways that play a crucial role in their expression and localization with potential implications for understanding mechanisms of neurodegenerative disease onset and progression.},
}

Animals
*tau Proteins/metabolism
*DNA-Binding Proteins/metabolism
*Neurons/metabolism/drug effects
Humans
*Signal Transduction/drug effects/physiology
*Insulin/pharmacology
Protein Isoforms/metabolism
HEK293 Cells
Mice
*Neurodegenerative Diseases/metabolism
Phosphorylation/drug effects
Cells, Cultured
Cerebral Cortex/cytology/metabolism
Mice, Inbred C57BL

@article {pmid41444088,
year = {2025},
author = {Lynch, S},
title = {Addressing Cognitive Dysfunction: Education, Diagnosis, and Practical Care.},
journal = {The Veterinary clinics of North America. Small animal practice},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cvsm.2025.09.030},
pmid = {41444088},
issn = {1878-1306},
abstract = {Cognitive dysfunction syndrome (CDS) is a common, yet underdiagnosed, neurobehavioral disease of domestic animals. Much like its human counterpart, Alzheimer's disease, CDS is the result of neuronal loss and inflammatory changes in the central nervous system; however, the specific pathophysiology of the disease continues to be researched in efforts to advance diagnostics, prognosis, and treatment. Diagnosis is typically conducted by ruling out possibilities and using assessment tools, including the Canine Dementia Scale and the Canine Cognitive Dysfunction Rating Scale. Treatment is often most successful when a tailored, multimodal approach is initiated early in the disease progression.},
}

@article {pmid41442238,
year = {2025},
author = {Periyakoil, VS and Von Gunten, C and Kraemer, H},
title = {Virtual, Nurse-Led Early Primary Palliative Care Intervention (ELICIT) for Community-Dwelling Older Adults With Cognitive Impairment: Protocol for a Randomized Controlled Trial.},
journal = {JMIR research protocols},
volume = {14},
number = {},
pages = {e75082},
pmid = {41442238},
issn = {1929-0748},
support = {R01 AG062239/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cognitive Dysfunction/nursing/therapy ; *Palliative Care/methods ; Aged ; Independent Living ; Male ; Female ; Aged, 80 and over ; Quality of Life ; Randomized Controlled Trials as Topic ; Primary Health Care ; },
abstract = {BACKGROUND: Although dementia is a serious illness that progresses over many years, little is known about the primary palliative care needs of individuals who have it, especially those living in the community.

OBJECTIVE: This trial aims to test the impact of a virtual, nurse-led early primary palliative care intervention (ELICIT) on older adults living in the community who are chronically ill and have a diagnosis of cognitive impairment or are at risk of it.

METHODS: A total of 200 community-dwelling older adults who were chronically ill and had varying degrees of cognitive impairment were recruited and randomized to either usual care or usual care + a virtual, nurse-led ELICIT. For both arms, we will track the number of participants who (1) report supportive care needs to the blinded evaluators and (2) complete conversations on goals of care and document advance directives and the Physician Orders for Life-Sustaining Treatment form in the electronic health record. We will also track their end-of-life resource use and the percentage of participants who receive goal-concordant care. Changes in Edmonton Symptom Assessment Scale, Patient Activation Measure, and Quality of Life in Alzheimer's Disease scores will be tracked and analyzed.

RESULTS: As of October 2025, we have recruited 200 participants. We are following all study participants on an ongoing basis to determine whether they received goal-concordant care at the end of life and their resource use patterns. We hypothesize that, compared to the usual care arm, more participants in the intervention arm will (1) express supportive care needs to the blinded evaluators, (2) complete goals of care conversations, document advance care planning, and (3) have higher levels of goal-concordant care and lower end-of-life resource use.

CONCLUSIONS: The identification of the primary palliative care needs of community-dwelling older adults who are chronically ill and have various levels of cognitive impairment will help refine the intervention and enable trained nurses to provide virtual early primary palliative care within the scope of nursing.},
}

Humans
*Cognitive Dysfunction/nursing/therapy
*Palliative Care/methods
Aged
Independent Living
Male
Female
Aged, 80 and over
Quality of Life
Randomized Controlled Trials as Topic
Primary Health Care

@article {pmid41441957,
year = {2025},
author = {Neve, V and Saqlain, S and Veeranjaneyulu, A and Karwa, P and Kapare, H and Yeralkar, K},
title = {Evaluation of the neuroprotective activity of Momordica dioica against aluminum chloride (AlCl3)-Induced alzheimer's disease in Wistar rats.},
journal = {Discover mental health},
volume = {5},
number = {1},
pages = {198},
pmid = {41441957},
issn = {2731-4383},
abstract = {Alzheimer's disease is a brain condition that slowly erodes a person's memory and cognitive abilities. It is caused by damage to brain cell, particularly in the hippocampus, a region crucial for memory. By 2050 worldwide no. of AD is going increases. Various therapeutic strategies have been explored for AD. The use of herbal products is one of the treatment regimens for AD. In this study, we examined how a herbal extract from Momordica dioica could potentially protect Wistar rats from AD caused by Aluminum chloride. Aluminum chloride (AlCl3) is widely used in preclinical studies to induce Alzheimer-like symptoms, as chronic exposure is known to promote oxidative stress, neuroinflammation, and cholinergic dysfunction-hallmarks of Alzheimer's disease pathology. A total of 86 Wistar rats were randomly assigned to nine experimental groups (n = 6-10 per group), including a normal control group and an Alzheimer's disease (AD) model group. One group treated with Donepezil (2.05 mg/kg), three groups treated with different doses of herbal extract of Momordica dioica (100, 200 and 400 mg/kg), and three groups treated with a combination of Donepezil and herbal extract of Momordica dioica (std + 100, std + 200 and std + 400 mg/kg). The aluminum chloride (17 mg/kg, p.o) was administered once daily for 7 days to induce AD. From the 8th day onward, the herbal extract of Momordica dioica was administered orally for 21 consecutive days at doses of 100, 200, and 400 mg/kg to groups 4, 5, and 6 respectively, as well as in combination with Donepezil (2.05 mg/kg) in groups 7, 8, and 9. This brought the total duration of the study to 28 days." Elevated Plus Maze and Forced Swim test was used for the behavioral assessment. After that, brain samples were collected for biochemical analysis. Herbal Extract significantly improved AlCl3-induced behavioral impairments and cognition deficits in Forced Swim Test, Elevated Plus Maze Test significantly with high dose. Then, herbal extract of Momordica dioica facilitated cholinergic activity via inhibiting acetylcholinesterase (AChE) activity. Besides, herbal extract of Momordica dioica decreased lipid peroxidation level & Nitrite level but enhanced levels of glutathione, Succinate dehydrogenase, Catalase and superoxide dismutase and results are more convincing with high dose. Histopathological analysis further confirmed reduced neuronal degeneration and better preservation of brain architecture, especially at higher doses of the herbal extract." The results suggested that herbal extract of Momordica dioica ameliorated AlCl3-induced cognitive and memory impairments, possibly through regulating AChE activity, suppressing oxidative stress. The herbal extract of Momordica dioica significantly improved behavioral impairments and cognition deficits, particularly at high doses. It facilitates cholinergic activity by inhibiting AChE activity and reduced oxidative stress. Overall, the conclusion states that the herbal extract may ameliorate and memory impairments associated with AD.},
}

@article {pmid41441560,
year = {2025},
author = {Clevenger, C and Jackson, WC and Stroud, J and Brubaker, M and Patel, M and Bucior, I and Bratlee-Whitaker, E and Brown, TM and Fehnel, S and Peschin, S and Cummings, J and Grossberg, G},
title = {Development and evaluation of the agitation in Alzheimer's screener for caregivers (AASC): a clinical tool to screen for agitation.},
journal = {Current medical research and opinion},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/03007995.2025.2606562},
pmid = {41441560},
issn = {1473-4877},
abstract = {OBJECTIVE: Although agitation is a common neuropsychiatric symptom in Alzheimer's dementia, it can be challenging to recognize and diagnose. Caregivers of individuals with Alzheimer's dementia are often the first to encounter agitation behaviors but may struggle to recognize and communicate symptoms to healthcare professionals (HCPs). Here, we describe the development and evaluation of the Agitation in Alzheimer's Screener for Caregivers (AASC), a practical screening tool to identify agitation symptoms and facilitate caregiver-HCP communication.

METHODS: The AASC was developed based on the International Psychogeriatric Association (IPA) criteria for agitation in cognitive disorders, input from multidisciplinary experts, and qualitative interviews with caregivers of patients with Alzheimer's dementia. Thereafter, a 2-phase quantitative evaluation study was conducted to refine the AASC and assess the predictive validity of the final tool against IPA criteria. Data were collected from caregiver-HCP dyads, where caregivers completed the AASC and HCPs used IPA criteria to inform their assessment of agitation.

RESULTS: A total of 226 caregiver-HCP dyads were quantitatively evaluated. The mean age of caregivers was 61 years; many were spouses/partners (46%), White (60%), and female (62%), providing an average of 60 h of care weekly (range: 9-168 h). Following initial assessment and refinement, the final AASC, evaluated in a subset of 105 dyads, showed a 73.3% agreement with IPA criteria, with sensitivity of 0.77, specificity of 0.70, and kappa and F1 scores of 0.47 and 0.71, respectively. Most patients were classified as having mild (41%) to moderate (37%) Alzheimer's dementia, while 22% had severe disease.

CONCLUSION: The AASC is a reliable, easy-to-use, 2-item screener for the presence and impact of agitation, in agreement with IPA criteria. The AASC supports caregivers and HCPs by providing an accessible framework for recognizing agitation throughout all stages of Alzheimer's dementia and prompting comprehensive assessment for diagnosis and appropriate treatment planning.},
}

@article {pmid41440958,
year = {2025},
author = {Rahmani, AR and Madani, SA and Aminov, E and Gogokhia, L and Bench, T and Kalogeropoulos, A},
title = {Heart Failure and Cognitive Impairment Through the Lens of the Gut Microbiome: A Narrative Review.},
journal = {Journal of personalized medicine},
volume = {15},
number = {12},
pages = {},
pmid = {41440958},
issn = {2075-4426},
abstract = {Heart failure (HF) affects over 55 million individuals globally, with prevalence projected to exceed 11 million in the United States by 2050 and is increasingly recognized as a systemic disorder extending beyond hemodynamic dysfunction to encompass profound alterations in neural and gut physiology. Cognitive impairment affects nearly half of HF patients and represents a major determinant of morbidity, self-care capacity, and mortality. Recent advances suggest that the gut microbiome serves as a pivotal intermediary in the heart-brain crosstalk, influencing neurocognitive outcomes through inflammatory, metabolic, and neurohumoral pathways. Dysbiosis in HF disrupts intestinal barrier integrity, facilitating translocation of endotoxins and microbial metabolites such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids, which in turn modulate neuroinflammation, cerebral perfusion, and neuronal signaling. The gut-heart-brain axis provides an integrative framework linking HF and cognitive impairment pathophysiology through dysbiosis-driven systemic inflammation and metabolite dysregulation. Gut-derived biomarkers and microbiome-targeted interventions represent promising strategies for detection of early alterations and precision treatment, highlighting the urge for prospective, multi-omics studies to establish causality and therapeutic efficacy. This review synthesizes current evidence connecting gut microbiome dysbiosis and metabolite alterations to both HF and cognitive impairment pathophysiology and proposes translational strategies for integrating microbiome-targeted therapies in HF patients with cognitive dysfunction.},
}

@article {pmid41438688,
year = {2026},
author = {Su, T and Li, Z and Yang, Y and Dai, Y and Li, Y and Zhao, H},
title = {In vitro 3D models of neuron-astrocyte interactions.},
journal = {Biochemistry and biophysics reports},
volume = {45},
number = {},
pages = {102400},
pmid = {41438688},
issn = {2405-5808},
abstract = {The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of in vitro 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of in vitro 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.},
}

@article {pmid41437993,
year = {2025},
author = {Fliri, A and Sostek, R and Kajiji, S},
title = {Protein swarm-based cause-effect analysis: effects of microRNAs on cooperation networks linking COVID-19 infections, atherosclerosis, and Alzheimer's disease.},
journal = {Frontiers in cardiovascular medicine},
volume = {12},
number = {},
pages = {1577844},
pmid = {41437993},
issn = {2297-055X},
abstract = {Well-being depends on the integrated operation of biological processes at all levels of system organization, from individual cells to tissues and organ systems, collectively sustaining homeostasis and optimal bodily functions. The regulation of cooperation among these processes is mediated by information flow within networks possessing diverse structural, functional, and temporal properties. Disruption in these networks is observed in conditions such as infections, inflammatory diseases, and cancer. To advance understanding of immune system roles and to elucidate mechanisms underlying health vulnerability during disease, we utilized proteomics data related to 4,800 diseases along with protein swarm-based cause-effect analyses to identify principles governing plasticity and self-organizing capabilities of immune systems. Our findings demonstrate that the precision of immune system functions is regulated by dynamic alterations in the topologies of cooperation networks that are partially modulated by microRNAs. Additionally, our analysis indicates that investigating the underlying causes of diseases through the study of cooperative network functions and their interactions with microRNAs-rather than concentrating exclusively on individual protein targets or microRNAs-provides significant insights for devising effective treatment strategies for infections, cardiovascular conditions, Alzheimer's disease, cancer, aging, and related health concerns.},
}

@article {pmid41436813,
year = {2025},
author = {Birnbaum, EM and Xie, L and Serrano, P and Rockwell, P and Figueiredo-Pereira, ME},
title = {BT-11 targets the LANCL2 pathway to attenuate cognitive deficits and hippocampal pathology in Alzheimer's transgenic rats.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-31514-z},
pmid = {41436813},
issn = {2045-2322},
support = {TL1-TR0002386//NIH Weill Cornell CTSC/ ; R01AG057555//NIH/NIA/ ; },
abstract = {Neuroinflammation is a key pathological hallmark of Alzheimer's disease (AD). Investigational and FDA approved drugs targeting inflammation already exist, thus drug repurposing for AD is a suitable approach. BT-11 is an investigational drug that reduces inflammation in the gut and improves cognitive function. BT-11 is orally active and binds to lanthionine synthetase C-like 2 (LANCL2), a glutathione-s-transferase, thus potentially reducing oxidative stress. We investigated the effects of BT-11 long-term treatment on the TgF344-AD rat model of AD. BT-11 (1) reduced spatial memory deficits, and hippocampal Abeta plaque load, and increased neuronal levels in males, and reduced microglia numbers in females, and (2) induced transcriptomic changes in signaling receptor, including G-protein coupled receptor pathways in both males and females, with changes in neurotrophic factors only in males. We detected LANCL2 in hippocampal nuclear and cytoplasmic fractions with potentially different post-translational modifications, suggesting distinct functions based on its subcellular localization. LANCL2 was present in oligodendrocytes, indicating a role in oligodendrocyte function. To our knowledge, these last two findings have not been reported. Overall, our data support that targeting LANCL2 with BT-11 improves cognition and reduces AD-like pathology potentially by modulating G-protein signaling. LANCL2's localization in oligodendrocytes suggest a possible role oligodendrocyte function that warrants further investigation. Our studies contribute to the field of new immunomodulatory AD therapeutics and establish LANCL2 as a promising therapeutic target meriting further mechanistic investigation.},
}

@article {pmid41435831,
year = {2025},
author = {Chaubey, K and Vázquez-Rosa, E and Tripathi, SJ and Shin, MK and Yu, Y and Dhar, M and Chakraborty, S and Yamakawa, M and Wang, X and Sridharan, PS and Miller, E and Bud, Z and Corella, SG and Barker, S and Caradonna, SG and Koh, Y and Franke, K and Cintrón-Pérez, CJ and Rose, S and Fang, H and Cintrón-Pérez, AA and Tomco, T and Zhu, X and Fujioka, H and Gefen, T and Flanagan, ME and Williams, NS and Wilson, BM and Chen, L and Dou, L and Cheng, F and Rexach, JE and Woo, JA and Kang, DE and Paul, BD and Pieper, AA},
title = {Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102535},
doi = {10.1016/j.xcrm.2025.102535},
pmid = {41435831},
issn = {2666-3791},
abstract = {Alzheimer's disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD[+]) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery and reduction of plasma levels of the clinical AD biomarker p-tau217. P7C3-A20 also reverses advanced disease in tau-driven PS19 mice and protects human brain microvascular endothelial cells from oxidative stress. In humans and mice, pathology severity correlates with disruption of brain NAD[+] homeostasis, and the brains of nondemented people with Alzheimer's neuropathology exhibit gene expression patterns suggestive of preserved NAD[+] homeostasis. Forty-six proteins aberrantly expressed in advanced 5xFAD mouse brain and normalized by P7C3-A20 show similar alterations in human AD brain, revealing targets with potential for optimizing translation to patient care.},
}

@article {pmid41434387,
year = {2025},
author = {Huang, X and Puri, R and Sun, D and Zhao, Y and Zhang, J and Huang, K and Wang, Y},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110031},
doi = {10.1002/alz70862_110031},
pmid = {41434387},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/physiopathology ; Female ; Male ; Aged ; Brain Mapping ; *Nerve Net/diagnostic imaging/physiopathology ; },
abstract = {BACKGROUND: Functional magnetic resonance imaging (fMRI) has emerged as a powerful modality for investigating brain activity, offering superior spatial resolution and a non-invasive means to probe functional connectivity. In the context of Alzheimer's disease (AD), studying these disruptions is crucial for understanding how functional connectivity changes in salient brain activation networks for different subtypes. This study compares asymptomatic and typical AD groups to identify early alterations in brain networks that may inform future diagnostic and therapeutic strategies.

METHOD: Three analytical pipelines were employed to characterize functional connectivity comprehensively from ADNI resting state fMRI data. The first pipeline parcellated the brain using functional atlases, then edge quantification through Graphical Lasso and group sparse covariance estimation, thereby capturing inter-regional dependencies, using Nilearn. The second pipeline used independent component analysis (ICA) to decompose the fMRI data into distinct spatial components; mutual information was then applied to quantify the statistical relationships among these components. The third pipeline utilized FSL to perform advanced brain decomposition techniques like ICA and dual regression to generate time series that were subsequently analyzed to discern significant connectivity patterns between asymptomatic and typical AD cohorts.

RESULT: Across all pipelines, heatmaps were generated to visualize regions of high and low brain activity, while network diagrams demonstrated varying levels of connectivity strength and hub distribution. For instance, when compared to typical AD, patients having asymptomatic AD have more regions with negative covariance. These regions are the right posterior temporal region, the default mode network. On the contrary, the regions with high positive connections or brain activity for typical AD are the auditory cortex, intraparietal sulcus, dorsal, ventral anterior cingulate cortex, and left lateral occipital complex. The posterior occipital region has strong negative connections with other regions of the brain in Typical AD.

CONCLUSION: This study underscores the utility of fMRI-based techniques for elucidating connectivity differences in asymptomatic and symptomatic stages of AD. By mapping out network-level alterations, the resulting brain graphs offer valuable insights into the pathophysiology of AD, highlighting regions and pathways that may be critical in the early detection and treatment of the disease, potentially in a clinical setting utilizing fMRI as a biomarker.},
}

Humans
*Alzheimer Disease/diagnostic imaging/physiopathology
*Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging/physiopathology
Female
Male
Aged
Brain Mapping
*Nerve Net/diagnostic imaging/physiopathology

@article {pmid41434278,
year = {2025},
author = {Honarvar, F and Noronha, J and Gibicar, A and Tyrrell, P and Maralani, P and Fischer, C and Black, SE and Moody, AR and Khademi, A},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110217},
doi = {10.1002/alz70862_110217},
pmid = {41434278},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *White Matter/diagnostic imaging/pathology ; Canada ; Biomarkers ; Cohort Studies ; *Alzheimer Disease/diagnostic imaging ; *Brain/diagnostic imaging/pathology ; Middle Aged ; *Cerebrovascular Disorders/diagnostic imaging ; Aged, 80 and over ; },
abstract = {BACKGROUND: Cerebrovascular disease (CVD) is a leading cause of mortality with a strong link to cognitive impairment and dementia. White matter lesions (WML) are prevalent in CVD and are early markers of vascular compromise, particularly in relation to intraplaque hemorrhage (IPH), an indicator of carotid artery plaque instability. As vascular disease represents a possible treatment window for dementia subjects, this study explores the relationship between hemispheric WML asymmetry and IPH utilizing a large multicenter cohort to find novel biomarkers of disease.

METHOD: FLAIR MRI scans of 264 subjects from the Canadian Atherosclerosis Imaging Network were categorized as IPH positive (IPH+) or IPH negative (IPH-) and WML biomarkers were automatically computed (Figure 1). Biomarkers related to WML prevalence (volume) and WML ischemia and progression (intensity) were extracted: ICV-normalized WML volume (WML-ICV), WML mean intensity (WML-Intensity), and WML intensity ratio (WML-IR). WML asymmetry was assessed via an asymmetry index measure (AIM). Linear mixed models and regression analyses were conducted, with adjustments for age, sex, scanner manufacturer, and stenosis, to evaluate associations between WML biomarkers and IPH status.

RESULT: IPH+ patients exhibited significant rightward asymmetry in WML-ICV (0.0032 ± 0.002, p < 0.05), WML-Intensity (7.26 ± 5.41, p < 0.05), and WML-IR (0.0271 ± 0.0204, p < 0.05); Table 1. IPH+ subjects (left, right or bilateral) had more lesions that were brighter in the right hemisphere. This trend was most pronounced in younger male patients (<65 years), suggesting a high-risk demographic. Regression analysis revealed IPH as a significant predictor of WML asymmetry, with stronger effects observed in subjects with IPH in the right carotid artery.

CONCLUSION: Previous studies suggest more injury in the right hemisphere for subjects with small vessel disease, and this work supports this finding. With rightward WML asymmetry being strongly associated with IPH, this could be reflecting a surrogate marker for overall vascular disease and its contribution to brain health and dementia. Automated WML biomarkers can be used to identify these high-risk patients and guide early interventions for subjects with vascular disease and dementia. Future work should validate these findings in larger, longitudinal datasets to enhance clinical applications.},
}

Humans
Male
Female
Magnetic Resonance Imaging
Aged
*White Matter/diagnostic imaging/pathology
Canada
Biomarkers
Cohort Studies
*Alzheimer Disease/diagnostic imaging
*Brain/diagnostic imaging/pathology
Middle Aged
*Cerebrovascular Disorders/diagnostic imaging
Aged, 80 and over

@article {pmid41434276,
year = {2025},
author = {Anda-Duran, I and Hwang, PH and Leverant, E and Emrani, S and Thompson, LI and Andersen, SL and Libon, DJ},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109843},
doi = {10.1002/alz70862_109843},
pmid = {41434276},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/psychology ; Aged ; *Alzheimer Disease/diagnosis ; *Neuropsychological Tests ; Aged, 80 and over ; Middle Aged ; Memory, Short-Term ; },
abstract = {BACKGROUND: With the availability of monoclonal anti-body treatment for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD), there is a need to screen and identify emergent disease as soon as possible. In a companion abstract, a panel of six novel outcome measures from the digital Trail Making Test-Part B (dTMT-B) was able to dissociate patients with mild cognitive impairment (MCI) versus normal cognition (NC). The current research fashioned an abbreviated dTMT-B test and assessed how well this test can dissociate patients with MCI versus NC; and relationships between paper/pencil neuropsychological tests.

METHOD: Using a digital neuropsychological battery of episodic and working memory tests, memory clinic patients (n = 58) were classified into groups presenting with MCI versus NC. An abbreviated dTMT-B test was created by examining behavior confined to approximately the first half of the test, i.e., target circle '1' through target circle 'F'. The panel of dTMT-B process metrics included (1) hit duration or time spent with the pen inside target circles; (2) distance or the length of an imaginary line connecting all targets; and (3) the velocity or the speed pen strokes were drawn.

RESULT: MCI patients were slightly older and less educated than NC patients; and scored lower on the MMSE. An ANOVA controlled for age, education, and sex found longer hit duration for MCI compared to NC patients (p < 0.004, η[2]= 0.204). No differences were found for total distance or pen stroke velocity. Partial correlations controlled for age, education, and sex found that longer hit duration inside target circles was associated with lower performance on tests measuring attention (WAIS-IV Digits Forward/ Trails A; r= -0.724, p < 0.001); working memory (WMS-IV Symbol Span/ letter fluency; r= -0.520, p < 0.007); and episodic memory (CVLT-9 Delay Free recall/ Recognition; r= -0.411, p < 0.037).

CONCLUSION: The engineering of the Trail Making Test- Part B onto the digital platform has resulted in a panel of new process-based metrics and potentially increases the versatility of this test. An abbreviated version of the test could easily be deployed to screen for emergent cognitive impairment.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/psychology
Aged
*Alzheimer Disease/diagnosis
*Neuropsychological Tests
Aged, 80 and over
Middle Aged
Memory, Short-Term

@article {pmid41434222,
year = {2025},
author = {Heston, MB and Windon, CC and Hanna, L and Gatsonis, C and Carrillo, MC and Apgar, C and Dilworth-Anderson, P and Hillner, BE and March, A and Siegel, BA and Whitmer, RA and Wilkins, CH and Joie, R and Rabinovici, GD},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110237},
doi = {10.1002/alz70862_110237},
pmid = {41434222},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/diagnostic imaging/drug therapy ; Aged ; *Positron-Emission Tomography ; Aged, 80 and over ; Brain/diagnostic imaging ; Socioeconomic Factors ; *Cognitive Dysfunction/diagnostic imaging/drug therapy ; },
abstract = {BACKGROUND: Socioeconomic vulnerabilities and healthcare environment contribute to disparities in dementia assessment. Whether these affect dementia management, however, remains unclear. We used Imaging Dementia - Evidence for Amyloid Scanning (IDEAS) study data to compare the impact of amyloid PET on pharmacological management across social factors, patient comorbidities, and physician practice settings.

METHODS: We analyzed rates of pharmacological change in IDEAS participants with visually interpretable amyloid PET, completed pre- and post-PET case reports, social determinants (racioethnic identity of Asian, Black, Hispanic, or White, area deprivation index (ADI), living arrangement, education) and medical history. Outcomes included any change between pre-PET and post-PET visits in prescription of Alzheimer's disease (AD) drugs, and of non-AD drugs treating dementia risk factors or affecting cognition/mood/behavior. We used multilevel logistic regression with a random site intercept to test whether the probability of change in management associated with social determinants, race/ADI interactions with amyloid-positivity, comorbidities, and clinical setting, adjusting for demographics.

RESULTS: Among 10,904 cognitively impaired participants (Table 1), 90% were White, with 4.8% Hispanic, 3.1% Black, and 1.8% Asian representation. 10% resided in highly disadvantaged neighborhoods (ADI 9-10), 83% lived with ≥1 person, and 68% were educated past high school. Pre-FDR correction (adjusted P-values: Table 1), AD drug management change was associated with dyslipidemia (OR [95% CI]=0.88 [0.80-0.97], P unadj=.007), depression (0.87 [0.77, 0.97], P unadj=.014), and tobacco use (0.87 [0.77, 0.99], P unadj=.028). Non-AD drug management change was associated with depression (1.73 [1.51, 1.97], P unadj<.001), group practice (0.72 [0.56, 0.93], P unadj=.012) and ADI in amyloid-positive participants (0.68 [0.47, 0.98], P unadj=.04). Change rates were also associated with amyloid-PET status, impairment level, and etiology. Figure 1 summarizes change rates across social factors.

CONCLUSIONS: These results suggest amyloid status, cognitive impairment level, dementia etiology, and comorbidities may inform pharmacological decision-making. Clarifying dementia etiology with amyloid PET may, for instance, help clinicians optimize treatment plans to address undermanaged depression in cognitively impaired older adults. Further, socioeconomic disadvantage may limit clinical response to amyloid-positivity. Replication in New IDEAS and examination of Medicare claims will help elucidate whether disparities in pre-PET management and management changes are primarily driven by access barriers to assessment and healthcare.},
}

Humans
Female
Male
*Alzheimer Disease/diagnostic imaging/drug therapy
Aged
*Positron-Emission Tomography
Aged, 80 and over
Brain/diagnostic imaging
Socioeconomic Factors
*Cognitive Dysfunction/diagnostic imaging/drug therapy

@article {pmid41434193,
year = {2025},
author = {Ackley, SF and Flanders, M and Chen, R and Wang, J and Shah, SJ},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e110201},
doi = {10.1002/alz70862_110201},
pmid = {41434193},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy ; Male ; Female ; Positron-Emission Tomography ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Aged ; *Cognitive Dysfunction/diagnostic imaging/drug therapy ; Aniline Compounds ; Ethylene Glycols ; Mental Status and Dementia Tests ; Amyloid beta-Peptides/metabolism ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: Amyloid removal has been used as surrogate outcomes in clinical trials of Alzheimer's disease (AD) drugs, leading to approvals of aducanumab and lecanemab under the Accelerated Approval Program. While well-established epidemiologic and econometric methods exist to formally evaluate amyloid's validity as a surrogate outcome, their application has been hindered by restricted access to individual-level data from anti-amyloid drug trials. The newly available individual-level data from the A4 trial of solanezumab offers a unique opportunity to demonstrate how these untapped approaches can improve our understanding of the impact of amyloid removal on cognitive decline.

METHOD: We used data on 815 A4 study participants (Alzheimer's Clinical Trial Consortium A4/LEARN) with complete follow-up measures for florbetapir PET imaging and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score. We estimated cognitive change using the trajectory of the CDR-SB score over 4.5 years. Instrumental-variable (IV) methods were used to evaluate the causal effect of amyloid reduction on cognitive changes using randomization as an instrument for amyloid reduction. Causal mediation analysis was conducted to estimate the extent to which changes in amyloid mediated the cognitive effects of solanezumab. Analyses were adjusted for sex, APOE-ε4 carrier status, and baseline age, cognition, and amyloid.

RESULT: Average between-group differences in amyloid change and cognitive trajectory were -0.05 (SD 0.16) SUVr and 0.002 (SD 0.028) CDR-SB points per month, respectively. Non-linear effects of amyloid on cognition were not supported (Figure 1). The IV-estimated effect of a 1 SUVr reduction on monthly CDR-SB change was -0.041, 95% CI: (-0.096, 0.014) (Figure 2). Mediation analysis suggests that amyloid change mediates 23% of solanezumab's effect on cognitive change, 95% CI: (-125%, 253%) (Figure 2).

CONCLUSION: Using epidemiologic and econometric methods to analyze individual-level data from trials of amyloid-targeting drugs will improve our understanding of amyloid as a surrogate outcome for cognition. In this instance, results are imprecise because solanezumab did not effectively remove amyloid. However, reproducing these analyses using individual-level data from effective anti-amyloid trials has the potential to shape treatment strategies and inform use of surrogate outcomes in future approval processes.},
}

Humans
*Alzheimer Disease/diagnostic imaging/drug therapy
Male
Female
Positron-Emission Tomography
*Antibodies, Monoclonal, Humanized/therapeutic use
Aged
*Cognitive Dysfunction/diagnostic imaging/drug therapy
Aniline Compounds
Ethylene Glycols
Mental Status and Dementia Tests
Amyloid beta-Peptides/metabolism
Brain/diagnostic imaging

@article {pmid41434192,
year = {2025},
author = {Chan, T and Rahmouni, N and Zheng, Y and Gonçalves, MP and Therriault, J and Macedo, AC and Trudel, L and Socualaya, KMQ and Hosseini, SA and Hall, BJ and Wang, YT and Aumont, E and Arias, JF and Bezgin, G and Servaes, S and Hopewell, R and Hsiao, C and Vitali, P and Pascoal, TA and Zetterberg, H and Benedet, A and Rosa-Neto, P},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109923},
doi = {10.1002/alz70862_109923},
pmid = {41434192},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/diagnosis/blood ; Female ; Male ; Aged ; Biomarkers/blood/cerebrospinal fluid ; *tau Proteins/blood/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Positron-Emission Tomography ; Cohort Studies ; Middle Aged ; Immunoassay ; Quebec ; Brain/diagnostic imaging/metabolism ; },
abstract = {BACKGROUND: With the anticipated arrival of disease-modifying treatments for Alzheimer's disease (AD) in Canada, integrating biomarkers into clinical practice is crucial to enhancing diagnostic accuracy and optimizing referrals for treatment. Lumipulse G1200 (Fujirebio) is a fully automated immunoassay instrument that streamlines the analysis of these biomarkers. In this study, we evaluated the diagnostic performance of Lumipulse G1200 plasma and CSF immunoassays in detecting AD pathology within a Quebec population cohort.

METHOD: Plasma and CSF samples of 102 participants from the TRIAD cohort (median age 67 years, 54% female) were analysed. Kruskal-Wallis with post hoc Benjamini-Hochberg false discovery rate (BH) correction compared the levels of biomarkers among the diagnostic groups. Discriminative performance for Aβ ([18]F-NAV4694) and tau ([18]F-MK6240) PET status was assessed using the area under the curve (AUC) of receiver operating characteristic (ROC). Amyloid PET global SUVR > 1.55 and tau PET metaROI SUVR>2.5STD of the young controls determined Aβ and Tau PET positivity, respectively. Spearman's correlation examined the association between plasma p-tau217 and p-tau181 with amyloid and tau PET SUVR.

RESULT: Plasma p-tau181 and p-tau217 were higher in individuals with clinical diagnosis of AD compared to the cognitively unimpaired (CU) or MCI not due to AD (MCI-). Plasma p-tau217 very strongly correlated with both Aβ and tau PET SUVR (ρ=0.805 and 0.797 respectively, p-value<2.2e-16), as compared to plasma p-tau181 (ρ=0.629 and 0.644 respectively, p < 4.097e-10). Both assays identified with comparable high accuracy elevated Aβ pathology (plasma p-tau217, AUC, 0.96, 95% CI: 0.92-1.00; p-tau181, AUC 0.88, CI 0.81- 0.96). However, plasma p-tau217 had higher discriminative performance than p-tau181 for tau PET (p-tau217, AUC 0.99, CI: 0.98-1.00; p-tau181, AUC 0.94, CI 0.89-0.98, DeLong's test p-value<0.01). CSF p-tau181, p-tau181/Aβ42 and Aβ42/40 had excellent discriminative performance for Aβ and tau PET positivity. Moreover, plasma p-tau217 had similar performance as CSF p-tau181 for predicting Aβ and tau PET positivity.

CONCLUSION: Lumipulse G1200 immunoassays showed excellent agreement with amyloid and tau PET. Their ease of use and high diagnostic accuracy make them strong candidates for clinical implementation.},
}

Humans
*Alzheimer Disease/diagnostic imaging/cerebrospinal fluid/diagnosis/blood
Female
Male
Aged
Biomarkers/blood/cerebrospinal fluid
*tau Proteins/blood/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid/blood
Positron-Emission Tomography
Cohort Studies
Middle Aged
Immunoassay
Quebec
Brain/diagnostic imaging/metabolism

@article {pmid41434191,
year = {2025},
author = {Condado, JG and Klinger, HM and Birkenbihl, C and Elorriaga, IT and Seto, M and Coughlan, GT and Properzi, MJ and Yang, HS and Erramuzpe, A and Rentz, DM and Schultz, AP and Chhatwal, JP and Johnson, KA and Cortes, JM and Sperling, RA and Hohman, TJ and Donohue, MC and Diez, I and Buckley, RF},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109903},
doi = {10.1002/alz70862_109903},
pmid = {41434191},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnostic imaging/pathology/genetics/metabolism ; Aged ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/pathology/metabolism ; tau Proteins/metabolism ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; Neuroimaging ; Longitudinal Studies ; *Cognitive Dysfunction/diagnostic imaging ; Cohort Studies ; *Aging/pathology ; Aged, 80 and over ; Biomarkers ; Middle Aged ; },
abstract = {BACKGROUND: BrainAge models estimate biological brain age based on neuroimaging data, providing a measure of brain health. This metric is particularly relevant in Alzheimer's disease (AD), where accelerated brain aging is exacerbated by β-amyloid (Aβ) and tau accumulation. We investigated the extent to which BrainAge moderates associations between AD biomarkers and longitudinal cognitive decline across two independent cohorts.

METHODS: We examined 1690 participants from A4/LEARN and 349 from HABS (Table 1). Using the Open-Source tool AgeML within each cohort, we built a BrainAge linear regressor model with 5-fold cross validation using MRI-T1 volumetric and FreeSurfer cortical thickness ROIs. We compared predicted ages with chronological age to create a BrainAgedelta. To avoid regressing out sex and APOEε4 variance, separate male/female models were built with data from APOEε4 non-carriers and applied to each cohort. We examined BrainAgedelta as a moderator of global neocortical Aβ-PET burden, temporal lobe Tau PET composite and p-tau217 associations with longitudinal PACC using linear mixed effects models. We adjusted for random intercepts and slopes, and baseline age, sex, years of education and APOEε4. In A4/LEARN we additionally adjusted for cumulative dose and treatment group using a spline model.

RESULTS: Higher levels of Aβ-PET, Tau-PET and p-tau217 at baseline was significantly correlated with higher BrainAgedelta (worse) (Figure 1). BrainAgedelta was directly associated with PACC trajectories in both cohorts. It also moderated the association between Aβ and Tau-PET and PACC trajectories such that higher BrainAgedelta was associated with faster cognitive decline with increasing levels of each biomarker. We found the same pattern of effects in p-tau217 limited only to the A4/LEARN sample but was trend-level in HABS (Figure 2).

CONCLUSIONS: BrainAgedelta is significantly associated with Aβ and tau burden and moderates their association with cognitive decline, supporting previous literature suggesting that BrainAge is a robust marker of brain health. Prioritizing individuals with worse BrainAge for clinical trials could not only effectively reduce screen fails (estimates forthcoming) but is a potentially feasible approach given that it can be calculated from a single T1-weighted MRI scan. These findings also highlight the importance of age-independent neurodegeneration patterns to contribute unique signal in models of brain health and pathological progression.},
}

Humans
Male
Female
*Alzheimer Disease/diagnostic imaging/pathology/genetics/metabolism
Aged
Magnetic Resonance Imaging
*Brain/diagnostic imaging/pathology/metabolism
tau Proteins/metabolism
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
Neuroimaging
Longitudinal Studies
*Cognitive Dysfunction/diagnostic imaging
Cohort Studies
*Aging/pathology
Aged, 80 and over
Biomarkers
Middle Aged

@article {pmid41434159,
year = {2025},
author = {Steward, A and Dewenter, A and Roemer-Cassiano, S and Biel, D and Zhu, Z and Frontzkowski, L and Hirsch, F and Klonowksi, M and Gnörich, J and Dehsarvi, A and Brendel, M and Franzmeier, N},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109847},
doi = {10.1002/alz70862_109847},
pmid = {41434159},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology ; *tau Proteins/cerebrospinal fluid/metabolism/blood ; Female ; Male ; *Apolipoprotein E4/genetics ; Aged ; Amyloid beta-Peptides/metabolism/cerebrospinal fluid ; Positron-Emission Tomography ; Biomarkers/cerebrospinal fluid ; Aged, 80 and over ; Brain/diagnostic imaging/metabolism ; Alleles ; Cross-Sectional Studies ; },
abstract = {BACKGROUND: Understanding factors influencing Alzheimer's disease (AD) progression is crucial for optimising treatment timing and targets. A major genetic risk factor, the Apolipoprotein E ε4 allele (ApoE4), is associated with earlier tau pathology accumulation and spread at lower amyloid-beta (Aβ) levels (Steward, JAMA Neurol, 2023). However, the mechanisms underlying this association remain unclear (Figure 1A). Therefore, we assessed how ApoE4 accelerates Aβ-related tau aggregation. Specifically, we investigated whether ApoE4 promotes Aβ-driven secretion of phospho tau (p-tau) or ptau dependent tau aggregation, and determined whether ApoE4 promotes tau pathology in an allele dose-dependent manner.

METHOD: We analysed data from APOE-genotyped AD-spectrum participants in the ADNI (n = 201) and A4 cohorts (n = 200), integrating cross-sectional fluid biomarker measures (plasma ptau217, CSF ptau181) and longitudinal Flortaucipir tau-PET and Florbetaben/Florbetapir amyloid-PET. Using linear regression, we assessed whether the interaction between amyloid-PET and ApoE4 allele dosage influences plasma ptau217, and replicated this analysis with CSF ptau181 in an ADNI subset (n = 115). Secondly, to investigate whether ApoE4 enhances tau fibrilisation and spread, we calculated annual tau-PET SUVR accumulation rates across a connectivity-based tau spreading stages, using our prior methodology (e.g. Franzmeier, Sci Adv, 2020). Linear regressions tested the interaction between ptau217 (or CSF ptau181) and ApoE4 allele count on connectivity-mediated tau-PET accumulation in four connectivity stages that capture progressive tau spread.

RESULT: ApoE4 allele dosage did not moderate the relationship between amyloid-PET and plasma ptau217 in either sample (Figure 1B, ADNI: β=0.13, p = 0.32; A4: β=-0.20, p = 0.17) nor between amyloid-PET and CSF ptau181 in ADNI subsample (Figure 1B, b=-.16, p = 0.42). However, a significant ApoE4 allele dose effect was observed in moderating the relationship between plasma ptau217 and tau-PET accumulation across connectivity stages independent of amyloid burden (Figure 1C, ADNI: Q1-4 mean β=0.44, Q1-4 p <0.001; A4: Q1-4 mean β = 0.56, Q1,2,4 p <0.001, Q3 p <0.05), with the strongest effect in individuals carrying two ApoE4 alleles.

CONCLUSION: ApoE4 exerts an allele dose-dependent effect on ptau induced tau aggregation, driving accelerated tau spreading at lower Aβ levels. This suggests that attenuating soluble ptau increases in ApoE4 carriers may mitigate downstream tau fibrilisation and delay dementia onset, highlighting the potential of personalised therapeutic approaches.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging/metabolism/pathology
*tau Proteins/cerebrospinal fluid/metabolism/blood
Female
Male
*Apolipoprotein E4/genetics
Aged
Amyloid beta-Peptides/metabolism/cerebrospinal fluid
Positron-Emission Tomography
Biomarkers/cerebrospinal fluid
Aged, 80 and over
Brain/diagnostic imaging/metabolism
Alleles
Cross-Sectional Studies

@article {pmid41434095,
year = {2025},
author = {Hu, M},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {Suppl 8},
pages = {e109822},
doi = {10.1002/alz70862_109822},
pmid = {41434095},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged ; Positron-Emission Tomography ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Disease Progression ; Aged, 80 and over ; Biomarkers ; *Brain/diagnostic imaging/metabolism ; Apolipoprotein E4/genetics ; },
abstract = {BACKGROUND: Despite advances in Alzheimer's disease (AD) research, limited information exists regarding the absolute risk of mild cognitive impairment (MCI) in cognitively unimpaired (CU) individuals with abnormal AD biomarkers, particularly when accounting for competing risks of death. This knowledge gap is critical as the field addresses disease-modifying treatments targeting CU individuals with preclinical AD. We focus on the predictive value of AD amyloid stages defined by amyloid PET Centiloid values.

METHODS: We included 5,858 participants from the Mayo Clinic Study of Aging (MCSA) to evaluate AD amyloid stage as a predictor of clinical progression to MCI or dementia. The data includes long-term follow-up information on death and dementia beyond active study participation, which mitigates potential bias due to dropout. We predicted 10-year and lifetime risks of MCI and dementia, accounting for the competing risks of death, given amyloid PET stages, sex, APOE4 status, and baseline age. Results are based on a hidden Markov model.

RESULTS: AD amyloid staging based on amyloid PET Centiloid values was the strongest predictor of lifetime risk for MCI or for dementia (Figure 1). Higher Centiloid levels amplified age effects on the risk of MCI, whereas for dementia, amyloid stage effects surpassed age effects. For 10-year risk, age was the dominant factor, whereas for lifetime risk, amyloid stages had a greater influence. While smaller in magnitude than the effects of amyloid stages and age, APOE4 carrier status and (on average) male sex were also associated with increased risk of MCI and dementia. For a female APOE4 carrier at age 65, lifetime risk was 41%/61%/76% for low/moderate/high amyloid PET levels. The 10-year absolute risk for a female APOE4 carrier with high amyloid PET was 4%/29%/58% when assessed at starting ages 65, 75, and 85.

CONCLUSIONS: AD amyloid staging is a critical predictor of lifetime risk for cognitive impairment, underscoring its importance in guiding treatment decisions if interventions are approved for preclinical AD in the future. Effective patient evaluation should focus on biomarker-based amyloid staging rather than simple binary biomarker classification, with careful consideration of age, sex, and APOE4 status to ensure a comprehensive benefit-risk assessment for future therapeutic strategies.},
}

Humans
Female
Male
*Alzheimer Disease/diagnostic imaging/metabolism
Aged
Positron-Emission Tomography
*Cognitive Dysfunction/diagnostic imaging/metabolism
Disease Progression
Aged, 80 and over
Biomarkers
*Brain/diagnostic imaging/metabolism
Apolipoprotein E4/genetics